Indazole compounds and uses thereof

ABSTRACT

Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.

FIELD OF THE INVENTION

The disclosure provides compounds as well as their compositions andmethods of use. The compounds modulate hematopoietic progenitor kinase 1(HPK1) activity and are useful in the treatment of various diseasesincluding cancer.

BACKGROUND OF THE INVENTION

Hematopoietic progenitor kinase 1 (HPK1) originally cloned fromhematopoietic progenitor cells is a member of MAP kinase kinase kinasekinases (MAP4Ks) family, which includes MAP4K1/HPK1, MAP4K2/GCK,MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK (Hu, M. C., et al.,Genes Dev, 1996. 10(18): p. 2251-64). HPK1 is of particular interestbecause it is predominantly expressed in hematopoietic cells such as Tcells, B cells, macrophages, dendritic cells, neutrophils, and mastcells (Hu, M. C., et al., Genes Dev, 1996. 10(18): p. 2251-64; Kiefer,F., et al., EMBO J, 1996. 15(24): p. 7013-25). HPK1 kinase activity hasbeen shown to be induced upon activation of T cell receptors (TCR)(Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), B cell receptors(BCR) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408),transforming growth factor receptor (TGF-βR) (Wang, W., et al., J BiolChem, 1997. 272(36): p. 22771-5; Zhou, G., et al., J Biol Chem, 1999.274(19): p. 13133-8), or G_(s)-coupled PGE2 receptors (EP2 and EP4)(Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96). As such,HPK1 regulates diverse functions of various immune cells.

HPK1 is important in regulating the functions of various immune cellsand it has been implicated in autoimmune diseases and anti-tumorimmunity (Shui, J. W., et al., Nat Immunol, 2007. 8(1): p. 84-91; Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48). HPK1 knockout micewere more susceptible to the induction of experimental autoimmuneencephalomyelitis (EAE) (Shui, J. W., et al., Nat Immunol, 2007. 8(1):p. 84-91). In human, HPK1 was downregulated in peripheral bloodmononuclear cells of psoriatic arthritis patients or T cells of systemiclupus erythematosus (SLE) patients (Batliwalla, F. M., et al., Mol Med,2005. 11(1-12): p. 21-9). Those observations suggested that attenuationof HPK1 activity may contribute to autoimmunity in patients.Furthermore, HPK1 may also control anti-tumor immunity via Tcell-dependent mechanisms. In the PGE2-producing Lewis lung carcinomatumor model, the tumors developed more slowly in HPK1 knockout mice ascompared to wild-type mice (see US 2007/0087988). In addition, it wasshown that adoptive transfer of HPK1 deficient T cells was moreeffective in controlling tumor growth and metastasis than wild-type Tcells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p.419-29). Similarly, BMDCs from HPK1 knockout mice were more efficient tomount a T cell response to eradicate Lewis lung carcinoma as compared towild-type BMDCs (Alzabin, S., et al., J Immunol, 2009. 182(10): p.6187-94). These data, in conjunction with the restricted expression ofHPK1 in hematopoietic cells and lack of effect on the normal developmentof immune cells, suggest that HPK1 is a drug target for enhancingantitumor immunity. Accordingly, there is a need for new compounds thatmodulate HPK1 activity.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient.

The present disclosure further provides methods of inhibiting HPK1activity, which comprises administering to an individual a compound ofthe disclosure, or a pharmaceutically acceptable salt thereof. Thepresent disclosure also provides uses of the compounds described hereinin the manufacture of a medicament for use in therapy. The presentdisclosure also provides the compounds described herein for use intherapy.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Compounds

The present disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN,NO₂, SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NOR^(a))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), S(O)₂NR^(c)R^(d) and BR^(h)R^(i); wherein said C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of the 5-10membered heteroaryl and 4-10 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2)NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g2);

R³ is selected from Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(e3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(e3)R^(d3),NR^(e3)R^(d3), NR^(e3)C(O)R^(b3), NR^(e3)C(O)OR^(a3),NR^(e3)C(O)NR^(e3)R^(d3), C(═NR^(e3))R^(b3), C(═NOR^(a3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), S(O)₂NR^(e3)R^(d3) andBR^(h3)R^(i3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

R^(X) is selected from H, D, Cy⁴, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(v1), SR^(v1), C(O)R^(w1),C(O)NR^(x1)R^(y1), C(O)OR^(x1), OC(O)R^(w1), OC(O)NR^(x1)R^(y1),NR^(x1)R^(y1), NR^(x1)C(O)R^(w1), NR^(x1)C(O)OR^(v1),NR^(x1)C(O)NR^(x1)R^(y1), C(═NR^(z1))R^(w1), C(═NOR^(v1))R^(w1),C(═NR^(z1))NR^(x1)R^(y1), NR^(x1)C(═NR^(z1))NR^(x1)R^(y1),NR^(x1)S(O)R^(w1), NR^(x1)S(O)₂R^(w1), NR^(x1)S(O)₂NR^(x1)R^(y1),S(O)R^(w1), S(O)NR^(x1)R^(y1), S(O)₂R^(w1), S(O)₂NR^(x1)R^(y1) andBR^(t1)R^(u1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

R^(Y) is selected from H, D, Cy⁵, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(v2), SR^(v2), C(O)R^(w2),C(O)NR^(x2)R^(y2), C(O)OR^(x2), OC(O)R^(w2), OC(O)NR^(x2)R^(y2),NR^(x2)R^(y2), NR^(x2)C(O)R^(w2), NR^(x2)C(O)OR^(v2),NR^(x2)C(O)NR^(x2)R^(y2), C(═NR^(z2))R^(w2), C(═NOR^(v2))R^(w2),C(═NR^(z2))NR^(x2)R^(y2), NR^(x2)C(═NR^(z2))NR^(x2)R^(y2),NR^(x2)S(O)R^(w2), NR^(x2)S(O)₂R^(w2), NR^(x2)S(O)₂NR^(x2)R^(y2),S(O)R^(w2), S(O)NR^(x2)R^(y2), S(O)₂R^(w2), S(O)₂NR^(x2)R^(y2) andBR^(t2)R^(u2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

wherein at least one of R^(X) and R^(Y) is other than H or D;

Cy³, Cy⁴, and Cy⁵ are each independently selected from C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryleach has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of the 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹³;

Cy^(B) is selected from C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-6 membered heteroaryl; wherein the4-10 membered heterocycloalkyl and 5-6 membered heteroaryl each has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of the 5-6membered heteroaryl and 4-10 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-6 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁷;

A is N or CR^(A);

R^(A) is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6)NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

R⁴ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g4);

R⁵ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), CO(O)R^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5)S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R⁷ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ alkylene, 5-10membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(e7))R^(b7),C(═NOR^(a7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),S(O)₂NR^(c7)R^(d7) and BR^(h7)R^(i7); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁸;

each R⁸ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ alkylene, 5-10membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), S(O)₂NR^(c8)R^(d8) and BR^(h8)R^(i8);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁹;

each R⁹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a9),SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), NR^(c9)R^(d9),NR^(c9)C(O)R^(b9), NR^(c9)C(O)OR^(a9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), (O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), and S(O)₂NR^(c9)R^(d9); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ alkylene, 5-10membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1)), (═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)R^(d1), S(O)₂ andBR^(h1)R^(i1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene,5-10 membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a11), SR^(a11),(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11), NR^(c11)R^(d11),NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11), NR^(c11)S(O)R^(b11),NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11),S(O)NR^(c11)R^(d11), S(O)₂R^(b11), S(O)₂NR^(c11)R^(d11) andBR^(h11)R^(i11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a12),SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12), C(O)OR^(a12),NR^(c12)R^(d12), NR^(c12)C(O)R^(b12), NR^(c12)C(O)OR^(a12),NR^(c12)S(O)R^(b12), NR^(c12)S(O)₂R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12),S(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12), NR^(c12)R^(d12)S(O)₂ andBR^(h12)R^(i12); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R¹³ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene,5-10 membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a13),SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13), OC(O)R^(b13),OC(O)NR^(c13)R^(d13), NR^(c13)R^(d13), NR^(c13)C(O)R^(b13),NR^(c13)C(O)OR^(a13), NR^(c13)C(O)NR^(c13)R^(d13), C(═NR^(e13))R^(b13),C(═NOR^(a13))R^(b13), C(═NR^(e13))NR^(c13)R^(d13),NR^(c13)C(═NR^(e13))NR^(c13)R^(d13), NR^(c13)S(O)R^(b13),NR^(c13)S(O)₂R^(b13), NR^(c13)S(O)₂NR^(c13)R^(d13), S(O)R^(b13),S(O)NR^(c13)R^(d13), S(O)₂R^(b13), S(O)₂NR^(c13)R^(d13),BR^(h13)R^(i13); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁴;

each R¹⁴ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene,5-10 membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a14), SR^(a14),(O)R^(b14), C(O)NR^(c14)R^(d14), C(O)OR^(a14), NR^(c14)R^(d14),NR^(c14)C(O)R^(b14), NR^(c14)C(O)OR^(a14), NR^(c14)S(O)R^(b14),NR^(c14)S(O)₂R^(b14), NR^(c14)S(O)₂NR^(c14)R^(d14), S(O)R^(b14),S(O)NR^(c14)R^(d14), S(O)₂R^(b14), S(O)₂NR^(c14)R^(d14) andBR^(h14)R^(i14); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁵;

each R¹⁵ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a15),SR^(a15), C(O)R^(b15), C(O)NR^(c15)R^(d15), C(O)OR^(a15),NR^(c15)R^(d15), NR^(c15)C(O)R^(b15), NR^(c15)C(O)OR^(a15),NR^(c15)S(O)R^(b15), NR^(c15)S(O)₂R^(b15), NR^(c15)S(O)₂NR^(c15)R^(d15),S(O)R^(b15), S(O)NR^(c15)R^(d15), S(O)₂R^(b15), S(O)₂R^(b15), andS(O)₂NR^(c15)R^(d15); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

or any R^(c) and R^(d) attached to the same N atom, together with the Natom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

each R^(b) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h) and R^(i) is independently selected from OH and C₁₋₆ alkoxy;

or any R^(h) and R^(i) attached to the same B atom are C₂₋₃ dialkoxy andtogether with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(e1) and R^(e11) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h1) and R^(e1) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h1) and R^(e1) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a1), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹³;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

each R^(e3) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h3) and R^(i3) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h3) and R^(i3) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl; each R^(a4),R^(c4) and R^(d4) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g); eachR^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a7), R^(c7) and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸;

each R^(e7) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h7) and R^(i7) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h7) and R^(i7) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁹;

or any R^(c8) and R^(d8) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁹;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁹;

each R^(h8) and R^(i8) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h8) and R^(i8) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl; each R^(a9),R^(c9) and R^(d9) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R^(b9) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a11), R^(c11) and R^(d11) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c11) and R^(d11) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b11) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(h11) and R^(i11) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h11) and R^(i11) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a12), R^(c12) and R^(d12) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b12) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(h12) and R^(i12) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h12) and R^(i12) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a13), R^(c13) and R^(d13) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁴;

or any R^(c13) and R^(d13) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁴;

each R^(b13) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁴;

each R^(e13) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(h13) and R^(i13) is independently selected from OH and C₁₋₆alkoxy;

or any R^(b13) and R^(i13) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a14), R^(c14) and R^(d14) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁵;

or any R^(c14) and R^(d14) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁵;

each R^(b14) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁵;

each R^(b14) and R^(i14) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h14) and R^(i14) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a15), R^(c15) and R^(d15) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b15) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(v1), R^(x1), and R^(y1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

or any R^(x1) and R^(y1) attached to the same N atom, together with theN atom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

each R^(w1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

each R^(z1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,amino sulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆ alkyl)aminosulfonyl;

each R^(t1) and R^(u1) is independently selected from OH and C₁₋₆alkoxy;

or any R^(t1) and R^(u1) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(v2), R^(x2), and R^(y2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

or any R^(x2) and R^(y2) attached to the same N atom, together with theN atom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

each R^(w2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

each R^(z2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(t2) and R^(u2) is independently selected from OH and C₁₋₆alkoxy;

or any R^(t2) and R^(u2) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, anddi(C₁₋₆alkyl)aminocarbonylamino;

each R^(g2) is independently selected from NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

each R^(g4) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, Cu-6 alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is selected from Cy¹ and NR^(c)R^(d);

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of the 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

R² is H;

R³ is selected from Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3)and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

R^(X) is selected from H, D, C₁₋₆ alkyl, CN, halo, C(O)NR^(x1)R^(y1),and Cy⁴; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³;

R^(Y) is selected from H, D, C₁₋₆ alkyl, CN, halo, C(O)NR^(x2)R^(y2),and Cy⁵; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³;

wherein at least one of R^(X) and R^(Y) is other than H or D;

Cy³, Cy⁴, and Cy⁵ are each independently is selected from C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10 memberedheteroaryl each has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of the 5-10 membered heteroaryl and4-10 membered heterocycloalkyl is optionally substituted by oxo to forma carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

Cy^(B) is phenyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

A is N or CR^(A);

R^(A) is H or C₁₋₃ alkyl;

R⁴ is H;

R⁵ is H;

each R⁷ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, 5-10 membered heteroaryl, halo, D, CN, NO₂,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7) and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁸;

each R⁸ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), S(O)₂R^(b8) and S(O)₂NR^(c8)R^(d8);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a1), SR^(a1), C(O)OR^(a1), OC(O)R^(b1), C(O)R^(b1),C(O)NR^(c1)R^(d1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1)NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a11); SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), C(O)OR^(a11), NR^(c11)S(O)R^(b11),NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11),S(O)NR^(c11)R^(d11), S(O)₂R^(b11), and S(O)₂NR^(c11)R^(d11);

each R¹³ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a13), SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13),OC(O)R^(b13), OC(O)NR^(c13)R^(d13), NR^(c13)R^(d13),NR^(c13)C(O)R^(b13), NR^(c13), C(O)OR^(a13),NR^(c13)C(O)NR^(c13)R^(d13), NR^(c13)S(O)R^(b13), NR^(c13)S(O)₂R^(b13),NR^(c13)S(O)₂NR^(c13)R^(d13), S(O)R^(b13), S(O)NR^(c13)R^(d13),S(O)₂R^(b13) and S(O)₂NR^(c13)R^(d13);

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

each R^(a7), R^(c7) and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸;

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(b8) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a11), R^(c11) and R^(d11) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(b11) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a13), R^(c13) and R^(d13) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(b13) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; and

each R^(x1), R^(y1), R^(x2), and R^(y2) is independently selected from Hand C₁₋₆ alkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is Cy¹;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of the 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

R² is H;

R³ is selected from Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3)and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

R^(X) is selected from H, D, C₁₋₆ alkyl, CN, halo, C(O)NR^(x1)R^(y1),and Cy⁴; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³;

R^(Y) is selected from H, D, C₁₋₆ alkyl, CN, halo, C(O)NR^(x2)R^(y2),and Cy⁵; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³;

wherein at least one of R^(X) and R^(Y) is other than H or D;

Cy³, Cy⁴, and Cy⁵ are each independently is selected from C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10 memberedheteroaryl each has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of the 5-10 membered heteroaryl and4-10 membered heterocycloalkyl is optionally substituted by oxo to forma carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

Cy^(B) is phenyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

A is N;

R⁴ is H;

R⁵ is H;

each R⁷ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7)and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸;

each R⁸ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), S(O)₂R^(b8) and S(O)₂NR^(c8)R^(d8);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a1); SR^(a1), C(O)R^(b1), C(O)OR^(a1), OC(O)R^(b1),C(O)NR^(c1)R^(d1); OC(O)NR^(c1)R^(d1); NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a11), SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11);S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11) and S(O)₂NR^(c11)R^(d11);

each R¹³ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a13), SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13),OC(O)R^(b13), OC(O)NR^(c13)R^(d13), NR^(c13)R^(d13),NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13), NR^(c13)C(O)NR^(c13)R^(d13),NR^(c13)S(O)R^(b13), NR^(c13)S(O)₂R^(b13), NR^(c13)S(O)₂NR^(c13)R^(d13),S(O)R^(b13); S(O)NR^(c13)R^(d13); S(O)₂R^(b13) and S(O)₂NR^(c13)R^(d13);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

each R^(a7), R^(c7) and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸;

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(b8) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a11), R^(c11) and R^(d11) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(b11) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a13), R^(c13) and R^(d13) is independently selected from H, C₁₋₆alkyl and C₁₋₆ haloalkyl;

each R^(b13) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; and

each R^(x1), R^(y1), R^(x2), and R^(y2) is independently selected from Hand C₁₋₆ alkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is Cy¹;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of 5-10 membered heteroaryland 4-10 membered heterocycloalkyl is optionally substituted by oxo toform a carbonyl group; and wherein the 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹);

R² is H;

R³ is selected from Cy³, C₁₋₆ alkyl, halo, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3) and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

R^(X) is selected from H, D, C₁₋₆ alkyl, CN, halo, C(O)NR^(x1), R^(y1),and Cy⁴; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³;

R^(Y) is selected from H, D, C₁₋₆ alkyl, CN, halo, C(O)NR^(x2)R^(y2),and Cy⁵; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³;

wherein at least one of R^(X) and R^(Y) is other than H or D;

Cy³, Cy⁴, and Cy⁵ are each independently is selected from C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10 memberedheteroaryl each has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of 5-10 membered heteroaryl and 4-10membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

Cy^(B) is phenyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

A is N;

R⁴ is H;

R⁵ is H;

each R⁷ is independently selected from C₁₋₆ alkyl, halo, D, CN, NO₂,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7); NR^(c7)R^(d7); NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7) and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸;

each R⁸ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), S(O)₂R^(b8) and S(O)₂NR^(c8)R^(d8);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1); S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a11), SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11) and S(O)₂NR^(c11)R^(d11);

each R¹³ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a13), SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13),OC(O)R^(b13), OC(O)NR^(c13)R^(d13), NR^(c13)R^(d13),NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13), NR^(c13)C(O)NR^(c13)R^(d13),NR^(c13)S(O)R^(b13), NR^(c13)S(O)₂R^(b13), NR^(c13)S(O)₂NR^(c13)R^(d13),S(O)R^(b13), S(O)NR^(c13)R^(d13), S(O)₂R^(b13) and S(O)₂NR^(c13)R^(d13);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, andC₁₋₆ alkyl.

each R^(b1) is independently selected from C₁₋₆ alkyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, andC₁₋₆ alkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

each R^(a7), R^(c7) and R^(d7) is independently selected from H and C₁₋₆alkyl;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸;

each R^(b7) is independently selected from C₁₋₆ alkyl;

each R^(a8), R^(c8) and R^(d8) is independently selected from H, andC₁₋₆ alkyl;

each R^(b8) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a11), R^(c11) and R^(d11) is independently selected from H, andC₁₋₆ alkyl;

each R^(b11) is independently selected from C₁₋₆ alkyl;

each R^(a13), R^(c13) and R^(d13) is independently selected from H, andC₁₋₆ alkyl;

each R^(b13) is independently selected from C₁₋₆ alkyl; and

each R^(x1), R^(y1), R^(x2), and R^(y2) is independently selected from Hand C₁₋₆ alkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is Cy¹;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of 5-10 membered heteroaryland 4-10 membered heterocycloalkyl is optionally substituted by oxo toform a carbonyl group; and wherein the 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰;

R² is H;

R³ is selected from Cy³, C₁₋₆ alkyl, halo, CN, and C(O)NR^(c3)R^(d3);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹³;

R^(X) is selected from H, D, C₁₋₆ alkyl, CN, halo, C(O)NR^(x1), R^(y1),and Cy⁴; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³;

R^(Y) is selected from H, D, C₁₋₆ alkyl, CN, halo, C(O)NR^(x2)R^(y2),and Cy⁵; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³;

wherein at least one of R^(X) and R^(Y) is other than H or D;

Cy³, Cy⁴, and Cy⁵ are each independently is selected from C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10 memberedheteroaryl each has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of 5-10 membered heteroaryl and 4-10membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

Cy^(B) is phenyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

A is N;

R⁴ is H;

R⁵ is H;

each R⁷ is independently selected from halo and OR^(a7);

each R⁸ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), S(O)₂R^(b8) and S(O)₂NR^(c8)R^(d8);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a11); SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),NR^(c11)R^(d11), NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(b11) and S(O)₂NR^(c11)R^(d11);

each R¹³ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a13), SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13),OC(O)R^(b13), OC(O)NR^(c13)R^(d13), NR^(c13)R^(d13),NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13), NR^(c13)C(O)NR^(c13)R^(d13),NR^(c13)S(O)R^(b13), NR^(c13)S(O)₂R^(b13), NR^(c13)S(O)₂NR^(c13)R^(d13),S(O)R^(b13), S(O)NR^(c13)R^(d13), S(O)₂R^(b13) and S(O)₂NR^(c13)R^(d13);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, andC₁₋₆ alkyl.

each R^(b1) is independently selected from C₁₋₆ alkyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, andC₁₋₆ alkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³;

each R^(a7), R^(c7) and R^(d7) is independently selected from H and C₁₋₆alkyl;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸;

each R^(b7) is independently selected from C₁₋₆ alkyl;

each R^(a8), R^(c8) and R^(d8) is independently selected from H, andC₁₋₆ alkyl;

each R^(b8) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a11), R^(c11) and R^(d11) is independently selected from H, andC₁₋₆ alkyl;

each R^(b11) is independently selected from C₁₋₆ alkyl;

each R^(a13), R^(c13) and R^(d13) is independently selected from H, andC₁₋₆ alkyl;

each R^(b13) is independently selected from C₁₋₆ alkyl; and

each R^(x1), R^(y1), R^(x2), and R^(y2) is independently selected from Hand C₁₋₆ alkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is Cy¹;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of 5-10 membered heteroaryland 4-10 membered heterocycloalkyl is optionally substituted by oxo toform a carbonyl group; and wherein the 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹);

R² is H;

R³ is selected from Cy³, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, andC(O)NR^(c3)R^(d3); wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹³;

R^(X) is selected from H, D, C₁₋₆ alkyl, CN, halo, andC(O)NR^(x1)R^(y1);

R^(Y) is selected from H, D, C₁₋₆ alkyl, CN, halo, and Cy⁵;

wherein at least one of R^(X) and R^(Y) is other than H or D;

Cy³ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein theC₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹³;

Cy⁵ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein5-10 membered heteroaryl each has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S;

Cy^(B) is phenyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

A is N;

R⁴ is H;

R⁵ is H;

each R⁷ is independently selected from halo and OR^(a7);

each R¹⁰ is independently selected from C₁₋₆ alkyl,OR^(a1)C(O)NR^(c1)R^(d1), NR^(c1)R^(d1), and NR^(c1)C(O)OR^(a1); whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R¹¹ is independently selected from OR^(a11) and NR^(c11)R^(d11),

each R¹³ is independently selected from C₁₋₆ alkyl, halo, D, CN, andOR^(a13);

each R^(a1), R^(c1) and R^(d1) is independently selected from H and C₁₋₆alkyl.

each R^(a7) is independently selected from H and C₁₋₆ alkyl;

each R^(a11), R^(c11) and R^(d11) is independently selected from H, andC₁₋₆ alkyl;

each R^(a13) is independently selected from H, and C₁₋₆ alkyl; and

each R^(x1) and R^(y1) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, R¹ is Cy¹.

In some embodiments, Cy¹ is selected from 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the4-10 membered heterocycloalkyl and 5-10 membered heteroaryl each has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of the 5-10 membered heteroaryl and 4-10membered heterocycloalkyl is optionally substituted by oxo; and whereinthe 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.

In some embodiments, Cy¹ is selected from 4-10 membered heterocycloalkyland 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl and4-10 membered heterocycloalkyl is optionally substituted by oxo; andwherein the 4-10 membered heterocycloalkyl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰.

In some embodiments, Cy¹ is selected from(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl;2,5-diazabicyclo[2.2.1]heptan-2-yl; diazabicycloheptanyl;(1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl;2,5-diazabicyclo[2.2.1]octan-2-yl; diazabicyclooctanyl; pyrrolidinyl;morpholinyl; 2,7-diazaspiro[4.4]nonan-2-yl; diazaspirononanyl;azetidinyl; pyrazolyl; piperidinyl; piperazinyl; and pyridinyl; whereineach Cy¹ is optionally substituted by oxo; and wherein each Cy¹ isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰.

In some embodiments, Cy¹ is selected from2,5-diazabicyclo[2.2.1]heptan-2-yl;5-(ethylcarbamoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl;4-amino-2-(hydroxymethyl)pyrrolidin-1-yl; 3-aminopyrrolidin-1-yl;2,5-diazabicyclo[2.2.1]octan-2-yl; 2-(hydroxymethyl)pyrrolidin-1-yl;morpholino; 6-oxo-2,7-diazaspiro[4.4]nonan-2-yl; 3-aminoazetidin-1-yl;2-(aminomethyl)pyrrolidin-1-yl; pyrrolidin-3-yl; 2-oxopyrrolidin-1-yl;1H-pyrazol-1-yl; o-tolyl; 3-aminopiperidin-1-yl; piperazin-1-yl;pyridin-3-yl; 1-methyl-1H-pyrazol-4-yl; 3-(hydroxymethyl)phenyl;2-(hydroxymethyl)phenyl; 3-((dimethylamino)methyl)phenyl; and4-(dimethylamino)piperidin-1-yl.

In some embodiments, Cy¹ is C₆₋₁₀ aryl optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹⁰.

In some embodiments, Cy¹ is phenyl optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹⁰.

In some embodiments, Cy¹ is selected from4-hydroxy-2-(aminomethyl)pyrrolidin-1-yl and3-(hydroxymethyl)piperazin-1-yl.

In some embodiments, Cy¹ is selected from2,5-diazabicyclo[2.2.1]heptan-2-yl;5-(ethylcarbamoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl;4-amino-2-(hydroxymethyl)pyrrolidin-1-yl; 3-aminopyrrolidin-1-yl;2,5-diazabicyclo[2.2.1]octan-2-yl; 2-(hydroxymethyl)pyrrolidin-1-yl;morpholino; 6-oxo-2,7-diazaspiro[4.4]nonan-2-yl; 3-aminoazetidin-1-yl;2-(aminomethyl)pyrrolidin-1-yl; pyrrolidin-3-yl; 2-oxopyrrolidin-1-yl;1H-pyrazol-1-yl; o-tolyl; 3-aminopiperidin-1-yl; piperazin-1-yl;pyridin-3-yl; 1-methyl-1H-pyrazol-4-yl; 3-(hydroxymethyl)phenyl;2-(hydroxymethyl)phenyl; 3-((dimethylamino)methyl)phenyl;4-(dimethylamino)piperidin-1-yl;4-hydroxy-2-(aminomethyl)pyrrolidin-1-yl and3-(hydroxymethyl)piperazin-1-yl.

In some embodiments, R¹ is NR^(c)R^(d).

In some embodiments, each R^(c) and R^(d) is independently selected fromH, C₁₋₆ alkyl, and 4-7 membered heterocycloalkyl, wherein said C₁₋₆alkyl and 4-7 membered heterocycloalkyl are each optionally substitutedwith 1, 2, or 3 substituents independently selected from R¹⁰.

In some embodiments, R² is H.

In some embodiments, R³ is selected from Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3) and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹³.

In some embodiments, R³ is selected from Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3) and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹³.

In some embodiments, R³ is selected from Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), andNR^(c3)C(O)NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³.

In some embodiments, R³ is selected from Cy³, C₁₋₆ alkyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹³.

In some embodiments, R³ is selected from C₁₋₆ alkyl, CN, halo,C(O)NR^(c3)R^(d3), and Cy³, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹³.

In some embodiments, R³ is halo. In some embodiments, R³ is F.

In some embodiments, R³ is C₁₋₆ alkyl, wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³.

In some embodiments, R³ is methyl.

In some embodiments, R³ is 2-hydroxyethyl

In some embodiments, R³ is CN.

In some embodiments, R³ is C(O)NR^(c3)R^(d3).

In some embodiments, R³ is 2-methoxyethyl. In some embodiments, R³ is2-fluoroethyl.

In some embodiments, R³ is Cy³.

In some embodiments, Cy³ is 4-10 membered heterocycloalkyl or 5-10membered heteroaryl, each of which is optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹³.

In some embodiments, Cy³ is 4-10 membered heterocycloalkyl, which isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³. In some embodiments, Cy³ is 4-10 memberedheterocycloalkyl. In some embodiments, Cy³ is tetrahydrofuranyl.

In some embodiments, Cy³ is 5-10 membered heteroaryl, which isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³. In some embodiments, Cy³ is 3-cyanopyridinyl.

In some embodiments, R^(X) is selected from H, D, Cy⁴, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(v1), SR^(v1),C(O)R^(w1), C(O)NR^(x1)R^(y1), C(O)OR^(x1), OC(O)R^(w1),OC(O)NR^(xi)R^(y1), NR^(x1)R^(y1)NR^(x1)C(O)R^(w1), NR^(x1)C(O)OR^(v1),and NR^(x1)C(O)NR^(x1)R^(y1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹³.

In some embodiments, R^(X) is selected from H, D, C₁₋₆ alkyl, CN, halo,and C(O)NR^(x1)R^(y1); wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹³. In someembodiments, R^(X) is halo. In some embodiments, R^(X) is F. In someembodiments, R^(X) is CN. In some embodiments, R^(X) is C₁₋₆ alkyl,wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹³. In some embodiments, R^(X)is methyl. In some embodiments, R^(X) is C(O)NR^(x1)R^(y1).

In some embodiments, R^(Y) is selected from H, D, Cy⁵, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, SR¹², C(O)R^(w2),C(O)NR^(x2)R^(y2), C(O)OR^(x2), OC(O)R^(w2), OC(O)NR^(x2)R^(y2),NR^(x2)R^(y1), NR^(x2)C(O)R^(w2), NR^(x2)C(O)OR^(v2), andNR^(x2)C(O)NR^(x2)R^(y2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³.

In some embodiments, R^(Y) is selected from H, D, C₁₋₆ alkyl, halo, andCy⁵; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or4 substituents independently selected from R¹³. In some embodiments,R^(Y) is halo. In some embodiments, R^(Y) is I. In some embodiments,R^(Y) is C₁₋₆ alkyl. In some embodiments, R^(Y) is methyl. In someembodiments, R^(Y) is Cy⁵.

In some embodiments, Cy⁵ is selected from C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryleach has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of the 5-10 membered heteroaryl and4-10 membered heterocycloalkyl is optionally substituted by oxo; andwherein the C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹³.

In some embodiments, Cy⁵ is C₆₋₁₀ aryl or 5-10 membered heteroaryl, eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³.

In some embodiments, Cy⁵ is C₆₋₁₀ aryl, wherein said C₆₋₁₀ aryl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³.

In some embodiments, Cy⁵ is phenyl, wherein said phenyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹³. In some embodiments, Cy⁵ is phenyl.

In some embodiments, Cy⁵ is 5-10 membered heteroaryl, wherein saidheteroaryl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³.

In some embodiments, Cy⁵ is pyrazolyl, wherein pyrazolyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹³. In some embodiments, Cy⁵ is 1-methyl-1H-pyrazol-4-yl.

In some embodiments, R^(x1) is selected from C₁₋₆ alkyl and H.

In some embodiments, R^(y1) is selected from C₁₋₆ alkyl and H.

In some embodiments, A is N.

In some embodiments, A is CR^(A).

In some embodiments, R^(A) is C₁₋₃ alkyl or H. In some embodiments,R^(A) is H.

In some embodiments, R⁴ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g4).

In some embodiments, R⁴ is selected from H, D, and C₁₋₆ alkyl.

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g).

In some embodiments, R⁵ is H.

In some embodiments, Cy^(B) is C₆₋₁₀ aryl optionally substituted with 1,2, 3, or 4 substituents independently selected from R⁷.

In some embodiments, Cy^(B) is phenyl optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁷.

In some embodiments, each R⁷ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂-6 alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7) and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁸.

In some embodiments, each R⁷ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), and NR^(c7)C(O)NR^(c7)R^(d7);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁸.

In some embodiments, each R⁷ is independently selected from C₁₋₆ alkyl,5-10 membered heteroaryl, halo, OR^(a7), C(O)NR^(c7)R^(d7),NR^(c7)R^(d7), wherein said C₁₋₆ alkyl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R⁸.

In some embodiments, each R⁷ is independently selected from halo andOR^(a7).

In some embodiments, each R⁸ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)C(O)R^(b8), S(O)₂R^(b8) andS(O)₂NR^(c8)R^(d8).

In some embodiments, each R⁸ is independently selected from C₁₋₆ alkyland D.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), andNR^(c1)C(O)OR^(a1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected fromC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), and C₁₋₆ alkyl; wherein saidC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), and C₁₋₆ alkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,OR^(a1), C(O)NR^(c1)R^(d1) and NR^(c1)R^(d1).

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a11), SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),C(O)OR^(a11), NR^(c11)R^(d11), NR^(c11)C(O)R^(b11),NR^(c11)C(O)OR^(a11), NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11), S(O)NR^(c11)R^(d11),S(O)₂R^(b11) and S(O)₂NR^(c11)R^(d11).

In some embodiments, each R¹¹ is independently selected from OR^(a11)and NR^(c11)R^(d11).

In some embodiments, each R¹³ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, NO₂, OR^(a13), SR^(a13), R^(b13), C(O)NR^(c13)R^(d13),C(O)OR^(a13), OC(O)R^(b13), OC(O)NR^(c13)R^(d13), NR^(c13)R^(d13),NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13), NR^(c13)C(O)NR^(c13)R^(d13),NR^(c13)S(O)R^(b13), NR^(c13)S(O)₂R^(b13), NR^(c13)S(O)₂NR^(c13)R^(d13),S(O)R^(b13), S(O)NR^(c13)R^(d13), S(O)₂R^(b13) and S(O)₂NR^(c13)R^(d13).

In some embodiments, each R¹³ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a13),SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13),NR^(c13)R^(d13), NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13), andNR^(c13)C(O)NR^(c13)R^(d13).

In some embodiments, each R¹³ is independently selected from C₁₋₆ alkyl,CN, and OR^(a13).

In some embodiments, R¹³ is OR^(a13).

In some embodiments, each R¹³ is independently selected from C₁₋₆ alkyl,halo, CN and OR^(a13). In some embodiments, R¹³ is CN.

In some embodiments, each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl.

In some embodiments, R^(c1) is selected from H and C₁₋₆ alkyl.

In some embodiments, R^(d1) is selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(b1) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl.

In some embodiments, each R^(a3), R^(c3) and R^(d3) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹³.

In some embodiments, R^(c3) is selected from C₁₋₆ alkyl and H.

In some embodiments, R^(d3) is selected from C₁₋₆ alkyl and H.

In some embodiments, each R^(b3) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³.

In some embodiments, each R^(a7), R^(c7) and R^(d7) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁸.

In some embodiments, each R^(a7), R^(c7) and R^(d7) are eachindependently selected from H and C₁₋₆ alkyl,

In some embodiments, R^(a7) is C₁₋₆ alkyl. In some embodiments, R^(a7)is methyl.

In some embodiments, or any R^(c7) and R^(d7) attached to the same Natom, together with the N atom to which they are attached, form a 4-,5-, 6- or 7-membered heterocycloalkyl group optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁸.

In some embodiments, each R^(b7) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸.

In some embodiments, each R^(a8), R^(c8) and R^(d8) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments, each R^(b8) is independently selected from C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments, each R^(a11), R^(c11) and R^(d11) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments, each R^(a11), R^(c11) and R^(d11) is independentlyselected from H and C₁₋₆ alkyl.

In some embodiments, R^(a11) is H.

In some embodiments, R^(c11) is selected from H and C₁₋₆ alkyl.

In some embodiments, R^(d11) is H.

In some embodiments, each R^(b11) is independently selected from C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments, each R^(a13), R^(c13) and R^(d13) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments, R^(a13) is selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(b13) is independently selected from C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments, provided herein is a compound having Formula IA:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁵, R^(X), Cy^(B), and A are as defined herein.

In some embodiments, provided herein is a compound having Formula IB:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁵, R^(Y), Cy^(B), and A are as defined herein.

In some embodiments, provided herein is a compound having Formula II:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or4, and wherein R¹, R³, R⁷, and R^(X) are as defined herein.

In some embodiments, provided herein is a compound having Formula III:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or4, and wherein R³, R⁷, and R^(X) are as defined herein.

In some embodiments, provided herein is a compound having Formula IV:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or4, and wherein R³, R⁷, and R^(Y) are as defined herein.

In some embodiments, provided herein is a compound having Formula V:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or4, and wherein R³, R⁷, and R^(Y) are as defined herein.

In some embodiments, provided herein is a compound having Formula VI:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or4, and wherein R³, R⁷, and R^(X) are as defined herein.

In some embodiments, provided herein is a compound selected from:

-   N-(4-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (1S,4S)—N-Ethyl-5-(7-fluoro-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-1-methyl-1H-indazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide;-   N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(4-(3-Aminopyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(4-(3-aminopyrrolidin-1-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-((1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(7-Fluoro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(7-fluoro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(7-Fluoro-1-methyl-4-morpholino-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(7-fluoro-2-methyl-4-morpholino-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(7-Fluoro-1-methyl-4-(6-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(7-fluoro-2-methyl-4-(6-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(3-Aminoazetidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(7-Fluoro-1-methyl-4-(pyrrolidin-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(7-Fluoro-1-methyl-4-(2-oxopyrrolidin-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(7-Fluoro-1-methyl-4-(1H-pyrazol-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(7-Fluoro-1-methyl-4-o-tolyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(7-Fluoro-2-methyl-4-o-tolyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(4-(3-aminopiperidin-1-yl)-7-cyano-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(4-(3-aminopiperidin-1-yl)-7-cyano-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)-4-(3-aminopiperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-N,    1-dimethyl-1H-indazole-7-carboxamide;-   (R)-4-(3-aminopiperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-N,2-dimethyl-2H-indazole-7-carboxamide;-   (R)—N-(4-(3-Aminopyrrolidin-1-yl)-7-fluoro-1-(2-hydroxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(1,7-Dimethyl-4-(piperazin-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carb    oxamide;-   N-(2,7-dimethyl-4-(piperazin-1-yl)-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(4-(3-aminopyrrolidin-1-yl)-1,7-dimethyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(7-Fluoro-1-methyl-4-(pyridin-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carb    oxamide;-   N-(7-Fluoro-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carb    oxamide;-   N-(7-Fluoro-4-(3-(hydroxymethyl)phenyl)-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carb    oxamide;-   N-(7-Fluoro-4-(2-(hydroxymethyl)phenyl)-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(3-((Dimethylamino)methyl)phenyl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-(2-hydroxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(4-(Dimethylamino)piperidin-1-yl)-3-iodo-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(4-(Dimethylamino)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-(4-(Dimethylamino)piperidin-1-yl)-1-methyl-3-phenyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;    and-   N-(4-(4-(Dimethylamino)piperidin-1-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound selected from:

-   N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   (R)—N-(7-Fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-1-(3-cyanopyridin-4-yl)-7-fluoro-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-((2S,4S)-2-(Aminomethyl)-4-hydroxypyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;    and-   N-(4-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-(2-fluoroethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound selected from:

-   N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-(methoxy-d₃)-3-methylphenyl)pyrimidine-4-carboxamide;-   N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(4-amino-2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;-   N-(4-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxy-3-(methylcarbamoyl)phenyl)pyrimidine-4-carboxamide;-   N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrimidine-4-carboxamide;-   (R)—N-(7-Fluoro-1-methyl-4-(methyl(piperidin-3-yl)amino)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;    and-   N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-6-(2-fluoro-6-methoxyphenyl)picolinamide,

or a pharmaceutically acceptable salt thereof.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C₁ alkyl”, refers to an alkyl group having n to mcarbon atoms. An alkyl group formally corresponds to an alkane with oneC—H bond replaced by the point of attachment of the alkyl group to theremainder of the compound. In some embodiments, the alkyl group containsfrom 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbonatoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, butare not limited to, chemical groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologssuch as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl,propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms. The term “C_(n-m) dialkoxy” refers to a linking groupof formula —O—(C_(n-m) alkyl)-O—, the alkyl group of which has n to mcarbons. Example dialkyoxy groups include —OCH₂CH₂O— and OCH₂CH₂CH₂O—.In some embodiments, the two 0 atoms of a C_(n-m) dialkoxy group may beattached to the same B atom to form a 5- or 6-membered heterocycloalkylgroup.

The term “amino” refers to a group of formula —NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula CN, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, C₁, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments,the haloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “oxidized” in reference to a ring-forming N atom refers to aring-forming N-oxide.

The term “oxidized” in reference to a ring-forming S atom refers to aring-forming sulfonyl or ring-forming sulfinyl.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, and the like. In some embodiments, arylgroups have from 6 to about 10 carbon atoms. In some embodiments arylgroups have 6 carbon atoms. In some embodiments aryl groups have 10carbon atoms. In some embodiments, the aryl group is phenyl. In someembodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3, or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3, or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl,thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-,1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, and 2,6-naphthyridine),indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, purinyl, and the like. In some embodiments, theheteroaryl group is pyridone (e.g., 2-pyridone).

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur, oxygen and phosphorus, and which has4-10 ring members, 4-7 ring members, or 4-6 ring members. Includedwithin the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and7-membered heterocycloalkyl groups. Heterocycloalkyl groups can includemono- or bicyclic (e.g., having two fused or bridged rings) orspirocyclic ring systems. In some embodiments, the heterocycloalkylgroup is a monocyclic group having 1, 2 or 3 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms andheteroatoms of a heterocycloalkyl group can be optionally oxidized toform an oxo or sulfido group or other oxidized linkage (e.g., C(O),S(O), C(S) or S(O)₂, N-oxide etc.) or a nitrogen atom can bequaternized. The heterocycloalkyl group can be attached through aring-forming carbon atom or a ring-forming heteroatom. In someembodiments, the heterocycloalkyl group contains 0 to 3 double bonds. Insome embodiments, the heterocycloalkyl group contains 0 to 2 doublebonds. Also included in the definition of heterocycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the heterocycloalkyl ring, e.g., benzo or thienylderivatives of piperidine, morpholine, azepine, etc. A heterocycloalkylgroup containing a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. Examples of heterocycloalkyl groups include2,5-diazabicyclo[2.2.1]heptanyl (e.g.,2,5-diazabicyclo[2.2.1]heptan-2-yl); pyrrolidinyl;2,5-diazabicyclo[2.2.1]octanyl; 2,5-diazabicyclo[2.2.2]octanyl (e.g.,2,5-diazabicyclo[2.2.2]octan-2-yl); morpholino;6-oxo-2,7-diazaspiro[4.4]nonanyl (e.g.,6-oxo-2,7-diazaspiro[4.4]nonan-2-yl); azetidinyl; 2-oxopyrrolidinyl;piperidinyl; and piperazinyl.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(9-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (9,unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007,7744-7765; The Organic Chemistry of Isotopic Labelling by James R.Hanson, Royal Society of Chemistry, 2011). Isotopically labeledcompounds can used in various studies such as NMR spectroscopy,metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et. al. J.Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm.2015, 58, 308-312).

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of Formula (I) can be prepared, e.g., using a process asillustrated in the schemes below.

Compounds of Formula (IA) with a variety of substitution at position R¹such as those described herein can be prepared using a process asillustrated in Scheme 1. In the process depicted in Scheme 1, anappropriately substituted 4-halo-1H-indazole 1-1 is nitrated using avariety of nitration conditions, including but not limited to nitricacid in the presence of sulfuric acid, to provide the correspondingnitrated derivative 1-2. Alkylation of the indazole using a suitableelectrophile in the presence of a suitable base (e.g. cesium carbonateor sodium hydride) or Mitsunobu displacement of a suitable alcohol inthe presence of triphenylphosphine and a suitable diimide, including butnot limited to diethylazidodicarboxylate or Cu-catalyzed amination(e.g., in the presence of Cu catalyst and a ligand, such as CuI andphenanthroline), provides compounds of general formula 1-3. The halosubstituent in 1-3 can be converted into the R¹ via a number of methods,including but not limited to nucleophilic displacement with anappropriate amine nucleophile in a suitable solvent (e.g., DMF, DMSO,dioxane) with a suitable base (e.g., triethylamine or DIPEA) or by asuitable cross-coupling, including but not limited to Buchwald (e.g. inthe presence of a palladacycle precatalyst, such as RuPhod Pd G2) andSuzuki (e.g., in the presence of a palladacycle precatalyst, such asXphos Pd G2), to give compounds of Formula 1-4. Examples ofcross-coupling procedures include Stille (ACS Catalysis 2015, 5,3040-3053) Suzuki (Tetrahedron 2002, 58, 9633-9695), Sonogashira (Chem.Soc. Rev. 2011, 40, 5084-5121), Negishi (ACS Catalysis 2016, 6,1540-1552), BuchwaldHartwig amination (Chem. Sci. 2011, 2, 27-50),Cu-catalyzed amination (Org. React. 2014, 85, 1-688) among others.Reduction of the nitro group with an appropriate reducing agent (e.g.,iron in the presence of ammonium chloride or hydrogen gas in thepresence of Pd/C catalyst) provides compounds of formula 1-5. Amide bondformation with an acid of formula 1-7 (e.g., using1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (“HATU”) and a base such as Hunig's base)provides compounds of desired Formula (IA).

The acids 1-7 can be prepared as illustrated in Scheme 2 by reaction ofa halogen containing compound (i.e., X=chloro, bromo or iodo) of formula1-6 and Cy^(B)-M (M=e.g., appropriately functionalized boron, stannyl orzinc species) using a cross coupling, such as Suzuki (e.g., in thepresence of a palladacycle precatalyst, such as Xphos Pd G2) or Stille(e.g., in the precense of a palladium catalyst such as (PPh₃)₂PdCl₂ anda base such as triethylamine).

Compounds of Formula (IB) with a variety of substitution at position R¹such as those described herein can be prepared using a process asillustrated in Scheme 3. In the process depicted in Scheme 3, anappropriately substituted 4-halo-1H-indazole 2-1 is nitrated using avariety of nitration conditions, i.e. nitric acid in the presence ofsulfuric acid, to provide the corresponding nitrated derivative 2-2.Iodination of 2-2 using standard conditions, i.e. NIS in an appropriatesolvent such as DMF, provides compounds of formula 2-3. Cross coupling(e.g., Suzuki in the presence of a paladium catalyst, such as PdCl₂dppf)provides compounds of formula 2-4. Alkylation of the indazole using asuitable electrophile in the presence of a suitable base (e.g., cesiumcarbonate or sodium hydride) or Mitsunobu displacement of a suitablealcohol in the presence of triphenylphosphine and a suitable diimide,e.g., diethylazidodicarboxylate or Cu-catalyzed amination (e.g., in thepresence of Cu catalyst and a ligand, such as CuI and phenanthroline),provides compounds of general formula 2-5. Compounds of formula 2-5 canbe converted into compounds of general formula (IB) in an analogousfashion to that described in Scheme 1 for compounds 1-5.

HPK1 Kinase

Studies have established that HPK1 is a negative regulator of T cell andB cell activation (Hu, M. C., et al., Genes Dev, 1996. 10(18): p.2251-64; Kiefer, F., et al., EMBO J, 1996. 15(24): p. 7013-25).HPK1-deficient mouse T cells showed dramatically increased activation ofTCR proximal signaling, enhanced IL-2 production, andhyper-proliferation in vitro upon anti-CD3 stimulation (Shui, J. W., etal., Nat Immunol, 2007. 8(1): p. 84-91). Similar to T cells, HPK1knockout B cells produced much higher levels of IgM and IgG isoformsafter KLH immunization and displayed hyper-proliferation potentially asa result of enhanced BCR signaling. Wang, X., et al., J Biol Chem, 2012.287(14): p. 11037-48. Mechanistically, during TCR or BCR signaling, HPK1is activated by LCK/ZAP70 (T cells) or SYK/LYN (B cells) mediated-Tyr379phosphorylation and its subsequent binding to adaptor protein SLP-76 (Tcells) or BLNK (B cells) (Wang, X., et al., J Biol Chem, 2012. 287(14):p. 11037-48). Activated HPK1 phosphorylates SLP-76 on Ser376 or BLNK onThr152, leading to the recruitment of signaling molecule 14-3-3 andultimate ubiquitination-mediated degradation of SLP-76 or BLNK (Liou,J., et al., Immunity, 2000. 12(4): p. 399-408; Di Bartolo, V., et al., JExp Med, 2007. 204(3): p. 681-91). As SLP-76 and BLNK are essential forTCR/BCR-mediated signaling activation (e.g. ERK, phospholipase Cγ1,calcium flux, and NFAT activation), HPK1-mediated downregulation ofthese adaptor proteins provide a negative feedback mechanism toattenuate signaling intensity during T cell or B cell activation (Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48).

The bone marrow-derived dendritic cells (BDMCs) from HPK1 knockout miceshowed higher expression of co-stimulatory molecules (e.g. CD80/CD86)and enhanced production of proinflammatory cytokines (IL-12, TNF-α etc),and demonstrated superior ability to stimulate T cell proliferation invitro and in vivo as compared to wild-type DCs (Alzabin, S., et al., JImmunol, 2009. 182(10): p. 6187-94). These data suggest that HPK1 isalso an important negative regulator of dendritic cell activation(Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). However,the signaling mechanisms underlying HPK-1 mediated negative regulationof DC activation remains to be elucidated.

In contrast, HPK1 appears to be a positive regulator of suppressivefunctions of regulatory T cells (Treg) (Sawasdikosol, S. et al., Thejournal of immunology, 2012. 188(supplement 1): p. 163). HPK1 deficientmouse Foxp3+ Tregs were defective in suppressing TCR-induced effector Tcell proliferation, and paradoxically gained the ability to produce IL-2following TCR engagement (Sawasdikosol, S. et al., The Journal ofImmunology, 2012. 188(supplement 1): p. 163). These data suggest thatHPK1 is an important regulator of Treg functions and peripheralself-tolerance.

HPK1 was also involved in PGE2-mediated inhibition of CD4+ T cellactivation (Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96).Studies published in US 2007/0087988 indicated that HPK1 kinase activitywas increased by exposure to physiological concentrations of PGE2 inCD4+ T cells and this effect was mediated by PEG2-induced PKAactivation. The proliferation of HPK1 deficient T cells was resistant tothe suppressive effects of PGE2 (see US 2007/0087988). Therefore,PGE2-mediated activation of HPK1 may represent a novel regulatorypathway of modulating immune response.

The present disclosure provides methods of modulating (e.g., inhibiting)HPK1 activity, by contacting HPK1 with a compound of the invention, or apharmaceutically acceptable salt thereof. In some embodiments, thecontacting can be administering to a patient a compound provided herein,or a pharmaceutically acceptable salt thereof. In certain embodiments,the compounds of the present disclosure, or pharmaceutically acceptablesalts thereof, are useful for therapeutic administration to enhance,stimulate and/or increase immunity in cancer. For example, a method oftreating a disease or disorder associated with inhibition of HPK1interaction can include administering to a patient in need thereof atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof. The compounds of the presentdisclosure can be used alone, in combination with other agents ortherapies or as an adjuvant or neoadjuvant for the treatment of diseasesor disorders, including cancers. For the uses described herein, any ofthe compounds of the disclosure, including any of the embodimentsthereof, may be used.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, triple-negativebreast cancer, colon cancer and lung cancer (e.g. non-small cell lungcancer and small cell lung cancer). Additionally, the disclosureincludes refractory or recurrent malignancies whose growth may beinhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited to,hematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiplemyeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia,hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angio sarcoma, fibro sarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma,and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angio sarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers.

In some embodiments, HPK1 inhibitors may be used to treat tumorsproducing PGE2 (e.g. Cox-2 overexpressing tumors) and/or adenosine (CD73and CD39 over-expressing tumors). Overexpression of Cox-2 has beendetected in a number of tumors, such as colorectal, breast, pancreaticand lung cancers, where it correlates with a poor prognosis.Overexpression of COX-2 has been reported in hematological cancer modelssuch as RAM (Burkitt's lymphoma) and U937 (acute promonocytic leukemia)as well as in patient's blast cells. CD73 is up-regulated in varioushuman carcinomas including those of colon, lung, pancreas and ovary.Importantly, higher expression levels of CD73 are associated with tumorneovascularization, invasiveness, and metastasis and with shorterpatient survival time in breast cancer.

As used herein, the term “contacting” refers to the bringing together ofthe indicated moieties in an in vitro system or an in vivo system suchthat they are in sufficient physical proximity to interact.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

I. Immune-Checkpoint Therapies

In some embodiments, the HPK1 inhibitors provided herein can be used incombination with one or more immune checkpoint inhibitors for thetreatment of cancer as described herein. Compounds of the presentdisclosure can be used in combination with one or more immune checkpointinhibitors. Exemplary immune checkpoint inhibitors include inhibitorsagainst immune checkpoint molecules such as CD20, CD28, CD39, CD40,CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM,arginase, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4,LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments,the immune checkpoint molecule is a stimulatory checkpoint moleculeselected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In someembodiments, the immune checkpoint molecule is an inhibitory checkpointmolecule selected from A2AR, B7-H₃, B7-H₄, BTLA, CTLA-4, IDO, KIR, LAG3,PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds of thedisclosure provided herein can be used in combination with one or moreagents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors,CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®),pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. Insome embodiments, the anti-PD-1 monoclonal antibody is nivolumab orpembrolizumab. In some embodiments, the anti-PD1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody isMGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Otheranti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g.urelumab, utomilumab).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 monoclonalantibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CSF1R, e.g., an anti-CSF1R antibody. In someembodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, IMP321, GSK2831781, orINCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MEDI6469,MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments,the OX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196. Anexample of an arginase inhibitor is CB-1158.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

II. Cancer Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Examples of agents that may be combined with compounds ofthe present disclosure include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway,inhibitors of beta catenin pathway, inhibitors of notch pathway,inhibitors of hedgehog pathway, inhibitors of Pim kinases, andinhibitors of protein chaperones and cell cycle progression. Targetingmore than one signaling pathway (or more than one biological moleculeinvolved in a given signaling pathway) may reduce the likelihood ofdrug-resistance arising in a cell population, and/or reduce the toxicityof treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors for the treatmentof diseases, such as cancer. Examples of cancers include solid tumorsand liquid tumors, such as blood cancers. For example, the compounds ofthe present disclosure can be combined with one or more inhibitors ofthe following kinases for the treatment of cancer: Akt1, Akt2, Akt3,TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4,c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer. Non-limiting examples of inhibitors thatcan be combined with the compounds of the present disclosure fortreatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 orFGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258,lucitanib, dovitinib, TAS-120, JNJ-42756493, Debio1347, INCB54828,INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g.,ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g.,epacadostat and NLG919), an LSD1 inhibitor (e.g., GSK2979552, INCB59872and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797and INCB50465), a PI3K-gamma inhibitor such as a PI3K-gamma selectiveinhibitor, a CSF1R inhibitor (e.g., PLX3397 and LY3022855), a TAMreceptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesisinhibitor, an interleukin receptor inhibitor, bromo and extra terminalfamily members inhibitors (for example, bromodomain inhibitors or BETinhibitors such as OTX015, CPI-0610, INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof. Inhibitors ofHDAC such as panobinostat and vorinostat. Inhibitors of c-Met such asonartumzumab, tivantnib, and INC-280. Inhibitors of BTK such asibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus. Inhibitors of Raf, such as vemurafenib anddabrafenib. Inhibitors of MEK such as trametinib, selumetinib andGDC-0973. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), PARP (e.g., olaparib) and Pim kinases(LGH447, INCB053914 and SGI-1776) can also be combined with compounds ofthe present disclosure.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include bendamustine, nitrogen mustards, ethylenimine derivatives,alkyl sulfonates, nitrosoureas and triazenes, uracil mustard,chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan,chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide. In some embodiments, theproteasome inhibitor is carfilzomib. In some embodiments, thecorticosteroid is dexamethasone (DEX). In some embodiments, theimmunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, CAR (Chimeric antigen receptor) T cell treatment as a boosterfor T cell activation, oncolytic virotherapy and immunomodulating smallmolecules, including thalidomide or JAK1/2 inhibitor and the like. Thecompounds can be administered in combination with one or moreanti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of: abarelix, abiraterone, afatinib,aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, amsacrine, anastrozole, aphidicolon, arsenic trioxide,asparaginase, axitinib, azacitidine, bevacizumab, bexarotene,baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib,buparlisib, busulfan intravenous, busulfan oral, calusterone, camptosar,capecitabine, carboplatin, carmustine, cediranib, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, crizotinib,cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin,dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine,degarelix, denileukin, denileukin diftitox, deoxycoformycin,dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolonepropionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin,epothilones, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole,leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel,pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin,ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab,rasburicase, regorafenib, reloxafine, revlimid, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,tegafur, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib,vinblastine, vincristine, vindesine, vinorelbine, vorinostat, andzoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 andPD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples ofantibodies to PD-1 and/or PD-L1 that can be combined with compounds ofthe present disclosure for the treatment of cancer or infections such asviral, bacteria, fungus and parasite infections include, but are notlimited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

Other anti-cancer agents include inhibitors of kinases associated cellproliferative disorder. These kinases include but not limited toAurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptorkinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3,JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk and SGK.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies. The steroids include butare not limited to 17 alpha-ethinylestradiol, diethylstilbestrol,testosterone, prednisone, fluoxymesterone, methylprednisolone,methyltestosterone, prednisolone, triamcinolone, chlorotrianisene,hydroxyprogesterone, aminoglutethimide, and medroxyprogesteroneacetate.

The compounds of the present disclosure can also be used in combinationwith lonafarnib (SCH6636), tipifarnib (R115777), L778123, BMS 214662,tezacitabine (MDL 101731), Sml1, triapine, didox, trimidox and amidox.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

In some embodiments, the compounds of the disclosure can be used incombination with INCB086550.

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or a pharmaceutically acceptable salt thereof, or any of the embodimentsthereof, and at least one pharmaceutically acceptable carrier orexcipient. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tert, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating HPK1 protein in tissuesamples, including human, and for identifying HPK1 ligands by inhibitionbinding of a labeled compound. Substitution of one or more of the atomsof the compounds of the present disclosure can also be useful ingenerating differentiated ADME (Adsorption, Distribution, Metabolism andExcretion). Accordingly, the present invention includes HPK1 bindingassays that contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium)¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²⁵I and ¹³¹I. For example, one or more hydrogen atoms in acompound of the present disclosure can be replaced by deuterium atoms(e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group of Formula (I)can be optionally substituted with deuterium atoms, such as CD3 beingsubstituted for CH₃). In some embodiments, alkyl groups in Formula (I)can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹Ior ³⁵S can be useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the invention can be used in a screening assay toidentify and/or evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a HPK1 protein by monitoring itsconcentration variation when contacting with the HPK1, through trackingof the labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known tobind to a HPK1 protein (i.e., standard compound). Accordingly, theability of a test compound to compete with the standard compound forbinding to the HPK1 protein directly correlates to its binding affinity.Conversely, in some other screening assays, the standard compound islabeled and test compounds are unlabeled. Accordingly, the concentrationof the labeled standard compound is monitored in order to evaluate thecompetition between the standard compound and the test compound, and therelative binding affinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of HPK1, such as cancer or infections, which include one ormore containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or any ofthe embodiments thereof. Such kits can further include one or more ofvarious conventional pharmaceutical kit components, such as, e.g.,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of HPK1 according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Hague, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check.

The compounds separated were typically subjected to analytical liquidchromatography mass spectrometry (LCMS) for purity check under thefollowing conditions: Instrument; Agilent 1100 series, LC/MSD, Column:Waters Sunfire™ C₁₈ 5 μm particle size, 2.1×5.0 mm, Buffers: mobilephase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient2% to 80% of B in 3 minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute. pH=10 purifications:Waters)(Bridge C₁₈ 5 μm particle size, 19×100 mm column, eluting withmobile phase A: 0.15% NH₄OH in water and mobile phase B: acetonitrile;the flow rate was 30 mL/minute, the separating gradient was optimizedfor each compound using the Compound Specific Method Optimizationprotocol as described in the literature [See “Preparative LCMSPurification: Improved Compound Specific Method Optimization”, K. Blom,B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)].Typically, the flow rate used with 30×100 mm column was 60 mL/minute.”

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD (N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA (N, N-diisopropylethylamine); DIBAL (diisobutylaluminium hydride);DMF (N, N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); FCC(flash column chromatography); g (gram(s)); h (hour(s)); HATU (N, N, N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate);HCl (hydrochloric acid); HPLC (high performance liquid chromatography);Hz (hertz); J (coupling constant); LCMS (liquid chromatography massspectrometry); LDA (lithium diisopropylamide); m (multiplet); M (molar);mCPBA (3-chloroperoxybenzoic acid); MS (Mass spectrometry); Me (methyl);MeCN (acetonitrile); MeOH (methanol); mg (milligram(s)); min.(minutes(s)); mL (milliliter(s)); mmol (millimole(s)); N (normal); nM(nanomolar); NMP (N-methylpyrrolidinone); NMR (nuclear magneticresonance spectroscopy); OTf (trifluoromethanesulfonate); Ph (phenyl);pM (picomolar); RP-HPLC (reverse phase high performance liquidchromatography); r.t. (room temperature), s (singlet); t (triplet ortertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (tripletof triplets); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg(microgram(s)); μL (microliter(s)); μM (micromolar); wt % (weightpercent).

Example 1.N-(4-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. 4-Bromo-7-fluoro-5-nitro-1H-indazole

A solution of 4-bromo-7-fluoro-1H-indazole (10 g, 46.5 mmol) in sulfuricacid (74.4 mL) at 0° C. was treated with nitric acid (18.60 mL)dropwise. The reaction mixture was warmed to room temperature andstirred for 30 mins. The mixture was then poured into ice and theresulting precipitate was collected by filtration and washed with water.The solid was air dried overnight and used in the next step withoutfurther purification (8.75 g, 70%). LCMS calculated for C₇H₄BrFN₃O₂(M+H)⁺: m/z=260.0/262.0; found 260.0/262.0.

Step 2. A mixture of 4-bromo-7-fluoro-1-methyl-5-nitro-1H-indazole and4-bromo-7-fluoro-2-methyl-5-nitro-2H-indazole

Procedure A. A suspension of 4-bromo-7-fluoro-5-nitro-1H-indazole (2.5g, 9.61 mmol) and potassium carbonate (6.64 g, 48.1 mmol) inacetonitrile (48.1 mL) was treated with methyl iodide (0.902 mL, 14.42mmol) and the resulting reaction mixture was stirred at room temperaturefor 5 hrs. The mixture was then treated with water and the desiredproduct was extracted with ethyl acetate. The combined organic phaseswere washed with water and brine, dried over sodium sulfate andconcentrated. The crude solid was used in the next step without furtherpurification (1.95 g, 74%). The product consisted of a 1:1 ratio ofregioisomers. Peak 1: LCMS calculated for C₈H₆BrFN₃O₂ (M+H)⁺:m/z=274.0/276.0; found 274.0/276.0. Peak 2: LCMS calculated forC₈H₆BrFN₃O₂ (M+H)⁺: m/z=274.0/276.0; found 274.0/276.0.

Procedure B. A solution of 4-bromo-7-fluoro-5-nitro-1H-indazole (500 mg,1.923 mmol) in ethyl acetate (9.615 mL) was treated withtrimethyloxonium tetrafluoroborate (370 mg, 2.500 mmol) and the reactionmixture stirred at room temperature overnight. The mixture was washed inturn with saturated aqueous sodium bicarbonate, water, and brine. Themixture was then dried over sodium sulfate and concentrated. The crudeproduct was used in the next step without further purification. Thisprocedure affords the 2H isomer. LCMS calculated for C₈H₆BrFN₃O₂ (M+H)⁺:m/z=274.0/276.0; found 274.0/276.0.

Step 3. 2-(2-Fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid

A mixture of 2-chloropyrimidine-4-carboxylic acid (9 g, 56.8 mmol),(2-fluoro-6-methoxyphenyl)boronic acid (11.58 g, 68.1 mmol), XPhos Pd G2(1.340 g, 1.703 mmol) and potassium phosphate (24.10 g, 114 mmol) wasmixed with 1,4-dioxane (100 mL) and water (20.00 mL). The reactionmixture was heated to 80° C. for 2 h under a nitrogen atmosphere. Thereaction mixture was then cooled to room temperature, treated with waterand diluted with ethyl acetate. The aqueous phase was separated, andacidified with 1 N HCl. The precipitated solid was collected byfiltration and washed with water. After air drying, the solid was usedin the next step without further purification. LCMS calculated forC₁₂H₁₀FN₂O₃ (M+H)⁺: m/z=249.2; found 249.2.

Step 4. A mixture of (1S,4S)-tert-butyl5-(7-fluoro-1-methyl-5-nitro-1H-indazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylateand (1S,4S)-tert-butyl5-(7-fluoro-2-methyl-5-nitro-2H-indazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A mixture of 4-bromo-7-fluoro-1-methyl-5-nitro-/H-indazole and4-bromo-7-fluoro-2-methyl-5-nitro-2H-indazole (from Step 2, 250 mg,0.912 mmol), tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (181 mg, 0.912mmol), BINAP (56.8 mg, 0.091 mmol), palladium(II) acetate (20.48 mg,0.091 mmol) and cesium carbonate (594 mg, 1.824 mmol) in toluene (3 mL)was stirred at 100° C. for 2 h under a nitrogen atmosphere. The mixturewas then diluted with dichloromethane and filtered through a pad ofCelite. The filtrate was concentrated and the resultant residue purifiedby Biotage Isolera™ (flash purification system with 20-100% ethylacetate in hexane) to provide the desired product (156 mg, 44%) as a 1:1mixture of regioisomers of the indazole core. Peak 1: LCMS calculatedfor C₁₈H₂₃FN₅O₄ (M+H)⁺: m/z=392.2; found 392.2. Peak 2: LCMS calculatedfor C₁₈H₂₃FN₅O₄ (M+H)⁺: m/z=392.2; found 392.2.

Step 5.N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution of tert-butyl(1S,4S)-5-(7-fluoro-1-methyl-5-nitro-1H-indazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylateand tert-butyl(1S,4S)-5-(7-fluoro-2-methyl-5-nitro-2H-indazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(156 mg, 0.399 mmol) in a 1:1:1 (v/v/v) mixture of THF/MeOH/water (4 mL)was treated with iron (89 mg, 1.594 mmol) and ammonium chloride (128 mg,2.391 mmol). The reaction mixture was heated to 80° C. for 1 h, cooledto room temperature, diluted with ethyl acetate and filtered through apad of Celite. The filtrate was washed with water and brine, dried oversodium sulfate and concentrated. The residue was treated with2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (109 mg, 0.438mmol), HATU (182 mg, 0.478 mmol), DMF (1993 μl) and Hunig's base (209μL, 1.196 mmol). The resulting mixture was stirred at room temperaturefor 30 mins and then treated with water. The resulting precipitate wascollected by filtration, washed with water and hexane, and air driedovernight. The crude solid was treated with TFA (3 mL) and the mixturewas stirred at room temperature for 30 mins. The mixture was thendiluted with methanol and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). Both the 1H and 2H isomers were isolated as theTFA salts of the title compounds. Peak 1 was assigned as the 2H isomer,and peak 2 was assigned as the 1H isomer. Peak 1: LCMS calculated forC₂₅H₂₄F₂N₇O₂ (M+H)⁺: m/z=492.2; Found: 492.2. ¹H NMR (500 MHz, DMSO) δ10.44 (s, 1H), 9.27 (d, J=5.0 Hz, 1H), 9.14 (s, 1H), 8.87 (s, 1H), 8.77(s, 1H), 8.15 (d, J=5.0 Hz, 1H), 7.63 (d, J=12.3 Hz, 1H), 7.61-7.51 (m,1H), 7.08 (d, J=8.5 Hz, 1H), 7.00 (t, J=8.8 Hz, 1H), 4.45 (s, 1H), 4.38(s, 1H), 4.19 (s, 3H), 3.78 (s, 3H), 3.70 (d, J=10.3 Hz, 1H), 3.48 (d,J=10.9 Hz, 1H), 3.32 (s, 1H), 3.18 (t, J=9.4 Hz, 1H), 2.03 (d, J=10.9Hz, 1H), 1.78 (d, J=10.5 Hz, 1H).

Peak 2: LCMS calculated for C₂₅H₂₄F₂N₇O₂ (M+H)⁺: m/z=492.2; Found:492.2. ¹H NMR (500 MHz, DMSO) δ 10.45 (s, 1H), 9.27 (d, J=5.0 Hz, 1H),9.07 (s, 1H), 8.78 (s, 1H), 8.37 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 7.72(d, J=12.7 Hz, 1H), 7.56 (q, J=8.4 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 7.00(t, J=8.8 Hz, 1H), 4.49 (s, 1H), 4.43 (s, 1H), 4.17 (s, 3H), 3.78 (s,3H), 3.76 (s, 1H), 3.51 (d, J=10.8 Hz, 1H), 3.32 (d, J=9.7 Hz, 1H),3.26-3.16 (m, 1H), 2.05 (d, J=10.7 Hz, 1H), 1.79 (d, J=10.6 Hz, 1H).

Example 2.(1S,4S)—N-Ethyl-5-(7-fluoro-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-1-methyl-1H-indazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

A solution ofN-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(from Example 1, Step 5; 10 mg, 0.0065 mmol) and hunig's base (9.4 μL,0.054 mmol) in dichloromethane (215 μL) was treated with ethylisocyanate (1.5 μL, 0.021 mmol). The reaction mixture was stirred at 60°C. for 1 h, diluted with methanol and purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% ammonium hydroxide, at flow rate of 60 mL/min). LCMS calculated forC₂₈H₂₉F₂N₈O₃ (M+H)⁺: m/z=563.2; Found: 563.2.

Example 3.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(4-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salts of the title compounds were prepared according to theprocedures described in Example 1, using tert-butyl(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate instead of tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. Peak 1: LCMS calculated for C₂₅H₂₆F₂N₇O₃ (M+H)⁺: m/z=510.2;Found: 510.2. Peak 2: LCMS calculated for C₂₅H₂₆F₂N₇O₃ (M+H)⁺:m/z=510.2; Found: 510.2. ¹H NMR (500 MHz, DMSO) δ 10.73 (s, 1H), 9.26(d, J=5.0 Hz, 1H), 8.34 (s, 1H), 8.26 (d, J=13.5 Hz, 1H), 8.17 (d, J=5.0Hz, 1H), 7.91 (s, 2H), 7.60-7.46 (m, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.00(t, J=8.7 Hz, 1H), 4.19 (s, 3H), 3.77 (s, 5H), 3.55 (dd, J=9.9, 4.9 Hz,1H), 3.43-3.29 (m, 2H), 3.17 (q, J=10.8, 9.8 Hz, 2H), 2.74-2.59 (m, 1H),1.83 (d, J=13.5 Hz, 1H).

Example 4.(R)—N-(4-(3-Aminopyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideand(R)—N-(4-(3-aminopyrrolidin-1-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salts of the title compounds were prepared according to theprocedures described in Example 1, using (R)-tert-butylpyrrolidin-3-ylcarbamate instead of tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. Peak 1: LCMS calculated for C₂₄H₂₄F₂N₇O₂ (M+H)⁺: m/z=480.2;Found: 480.2. Peak 2: LCMS calculated for C₂₄H₂₄F₂N₇O₂ (M+H)⁺:m/z=480.2; Found: 480.2. Peak 2: ¹H NMR (500 MHz, DMSO) δ 10.94 (s, 1H),9.28 (d, J=5.0 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.14 (d, J=5.0 Hz, 1H),8.12 (d, J=13.2 Hz, 1H), 8.07 (s, 1H), 7.58 (q, J=8.4 Hz, 1H), 7.09 (d,J=8.5 Hz, 1H), 7.03 (t, J=8.8 Hz, 1H), 4.18 (s, 3H), 3.79 (s, 3H),3.68-3.57 (m, 2H), 3.51 (q, J=8.2 Hz, 2H), 3.29 (dd, J=9.3, 5.1 Hz, 1H),3.21 (td, J=8.5, 3.4 Hz, 1H), 2.06 (dq, J=16.1, 8.1 Hz, 1H), 1.97-1.88(m, 1H).

Example 5.N-(4-((1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salts of the title compounds were prepared according to theprocedures described in Example 1, using (1S,4S)-tert-butyl2,5-diazabicyclo[2.2.2]octane-2-carboxylate instead of tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. Peak 1: LCMS calculated for C₂₆H₂₆F₂N₇O₂ (M+H)⁺: m/z=506.2;Found: 506.2. Peak 2: LCMS calculated for C₂₆H₂₆F₂N₇O₂ (M+H)⁺:m/z=506.2; Found: 506.2.

Example 6.(R)—N-(7-Fluoro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideand(R)—N-(7-fluoro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salts of the title compounds were prepared according to theprocedures described in Example 1, using (R)-pyrrolidin-2-ylmethanolinstead of tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. Peak 1: LCMS calculated for C₂₅H₂₅F₂N₆O₃ (M+H)⁺: m/z=495.2;Found: 495.2. Peak 2: LCMS calculated for C₂₅H₂₅F₂N₆O₃ (M+H)⁺:m/z=495.2; Found: 495.2.

Example 7.N-(7-Fluoro-1-methyl-4-morpholino-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(7-fluoro-2-methyl-4-morpholino-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salts of the title compounds were prepared according to theprocedures described in Example 1, using morpholine instead oftert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate asstarting material. Peak 1: LCMS calculated for C₂₄H₂₃F₂N₆O₃ (M+H)⁺:m/z=481.2; Found: 481.2. Peak 2: LCMS calculated for C₂₄H₂₃F₂N₆O₃(M+H)⁺: m/z=481.2; Found: 481.2.

Example 8.N-(7-Fluoro-1-methyl-4-(6-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(7-fluoro-2-methyl-4-(6-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salts of the title compounds were prepared according to theprocedures described in Example 1, using 2,7-diazaspiro[4.4]nonan-1-oneinstead of tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. Peak 1: LCMS calculated for C₂₇H₂₆F₂N₇O₃ (M+H)⁺: m/z=534.2;Found: 534.2. Peak 2: LCMS calculated for C₂₇H₂₆F₂N₇₀₃ (M+H)⁺:m/z=534.2; Found: 534.2.

Example 9.N-(4-(3-Aminoazetidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 1, using tert-butylazetidin-3-ylcarbamate instead of tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₃H₂₂F₂N₇O₂ (M+H)⁺: m/z=466.2; Found:466.2.

Example 10.(R)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideand(R)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salts of the title compounds were prepared according to theprocedures described in Example 1, using (R)-tert-butylpyrrolidin-2-ylmethylcarbamate instead of tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. Peak 1: LCMS calculated for C₂₅H₂₆F₂N₇O₂ (M+H)⁺: m/z=494.2;Found: 494.2. Peak 2: LCMS calculated for C₂₅H₂₆F₂N₇O₂ (M+H)⁺:m/z=494.2; Found: 494.2.

Example 11.N-(7-Fluoro-1-methyl-4-(pyrrolidin-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl3-(5-amino-7-fluoro-1-methyl-1H-indazol-4-yl)pyrrolidine-1-carboxylate

A mixture of 4-bromo-7-fluoro-1-methyl-5-nitro-1H-indazole and4-bromo-7-fluoro-2-methyl-5-nitro-2H-indazole (from Example 1, Step 2;200 mg, 0.730 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(323 mg, 1.095 mmol), XPhos Pd G2 (57.4 mg, 0.073 mmol) and potassiumphosphate, tribasic (310 mg, 1.460 mmol) was taken up in 1,4-dioxane (2mL) and water (405 μL). The reaction mixture was stirred at 80° C. for 1h under a nitrogen atmosphere. The mixture was then cooled to roomtemperature, diluted with dichloromethane and filtered through a pad ofCelite. The filtrate was concentrated, and the residue purified byBiotage Isolera™ (flash purification system with ethyl acetate/hexane ata ratio from 0 to 100%) to afford the desired product.

The residue was dissolved in a 1:1 (v/v) mixture of ethanol/methanol (4mL) and treated with palladium hydroxide on carbon (102 mg, 0.146 mmol).The reaction flask was evacuated, back filled with hydrogen gas from aballoon and then stirred at 60° C. overnight. The reaction mixture wasdiluted with methanol, filtered through a pad of Celite, diluted furtherwith ethyl acetate and then concentrated. The crude product was used inthe next step without further purification. LCMS calculated forC₁₇H₂₄FN₄O₂ (M+H)⁺: m/z=335.2; Found: 335.2.

Step 2.N-(7-fluoro-1-methyl-4-(pyrrolidin-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(65.3 mg, 0.263 mmol), tert-butyl3-(5-amino-7-fluoro-1-methyl-1H-indazol-4-yl)pyrrolidine-1-carboxylate(80 mg, 0.239 mmol) and HATU (109 mg, 0.287 mmol) was treated with DMF(1196 μL) and Hunig's base (125 μL, 0.718 mmol). The reaction mixturewas stirred at room temperature for 30 min and then treated with water.The resulting precipitate was collected by filtration, washed with waterand hexane, and air dried. The solid was dissolved in TFA (1 mL) andallowed to stand for 30 mins at room temperature. The TFA solution wasdiluted with MeOH and the sample was purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to provide the TFA salt of thetitle compound. LCMS calculated for C₂₄H₂₃F₂N₆O₆ (M+H)⁺: m/z=465.2;Found: 465.2.

Example 12.N-(7-Fluoro-1-methyl-4-(2-oxopyrrolidin-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. 1-(7-fluoro-1-methyl-5-nitro-1H-indazol-4-yl)pyrrolidin-2-one

A mixture of 4-bromo-7-fluoro-1-methyl-5-nitro-1H-indazole and4-bromo-7-fluoro-2-methyl-5-nitro-2H-indazole (from Example 1, Step 2;50 mg, 0.182 mmol), Pd₂(dba)₃ (16.71 mg, 0.018 mmol), Xantphos (10.56mg, 0.018 mmol) and cesium carbonate (178 mg, 0.547 mmol) was treatedwith 1,4-dioxane (912 μL) and pyrrolidin-2-one (28.0 μL, 0.365 mmol).The reaction mixture was stirred at 90° C. overnight under a nitrogenatmosphere. The mixture was then diluted with dichloromethane andfiltered through a pad of Celite. The filtrate was concentrated and theresidue purified by Biotage Isolera™ (flash purification system withethyl acetate/hexane at a ratio from 35 to 100%, thenmethanol/dichloromethane 0-20%) to provide the desired product (50 mg,100%). LCMS calculated for C₁₂H₁₂FN₄O₃ (M+H)⁺: m/z=279.2; Found: 279.2.

Step 2.N-(7-fluoro-1-methyl-4-(2-oxopyrrolidin-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution of1-(7-fluoro-1-methyl-5-nitro-1H-indazol-4-yl)pyrrolidin-2-one (48 mg,0.173 mmol) in a 1:1:1 (v/v/v) mixture of THF/MeOH/Water (1.5 mL) wastreated with iron (38.5 mg, 0.690 mmol) and ammonium chloride (55.4 mg,1.035 mmol). The reaction mixture was heated to 80° C. for 1 h, thencooled to room temperature, diluted with ethyl acetate and filteredthrough a pad of Celite. The filtrate was washed with water and brine,dried over sodium sulfate and concentrated. The residue was combinedwith 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (42.8 mg,0.173 mmol) and HATU (72.2 mg, 0.190 mmol) and then the mixture wastreated with DMF (863 μL) and Hunig's base (90 μL, 0.518 mmol). Thereaction mixture was stirred at room temperature for 30 min, and thentreated with water. The resulting precipitate was collected byfiltration, washed with water and hexane, and then dissolved inacetonitrile and purified with prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min) to provide the TFA salt of the title compound. LCMScalculated for C₂₄H₂₁F₂N₆O₃ (M+H)⁺: m/z=479.2; Found: 479.2.

Example 13.N-(7-Fluoro-1-methyl-4-(1H-pyrazol-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. 7-fluoro-1-methyl-5-nitro-4-(1H-pyrazol-1-yl)-1H-indazole

A solution of 1H-pyrazole (12.42 mg, 0.182 mmol) in DMF (1800 μL) wastreated with sodium hydride (8.76 mg, 0.219 mmol) and the reactionmixture stirred at room temperature for 5 min.4-bromo-7-fluoro-1-methyl-5-nitro-1H-indazole (50 mg, 0.182 mmol) wasthen added and stirring was continued for 3 hrs at room temperature. Themixture was then treated with water and extracted with ethyl acetate.The combined organic phases were washed with water and brine, dried oversodium sulfate and concentrated. The crude product was used in the nextstep without further purification. LCMS calculated for C₁₁H₉FN₅O₂(M+H)⁺: m/z=262.2; Found: 262.2.

Step 2.N-(7-Fluoro-1-methyl-4-(1H-pyrazol-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution of 7-fluoro-1-methyl-5-nitro-4-(1H-pyrazol-1-yl)-1H-indazole(45 mg, 0.172 mmol) in a 1:1:1 (v/v/v) mixture of MeOH/THF/Water (1.5mL) was treated with iron (9.6 mg, 0.172 mmol) and ammonium chloride(9.2 mg, 0.172 mmol). The reaction mixture was heated to 80° C. for 1 h,cooled to room temperature, diluted with ethyl acetate and filteredthrough a pad of Celite. The filtrate was washed with water and brine,dried over sodium sulfate, and concentrated. To the residue was added2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (42.8 mg, 0.172mmol) and HATU (65.5 mg, 0.172 mmol) followed by DMF (1700 μL) andHunig's base (30 μL, 0.172 mmol). The reaction mixture was stirred atroom temperature for 30 min, then treated with water. The resultingprecipitate was collected by filtration, washed with water and hexane,and then dissolved in acetonitrile/TFA and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to provide the TFA saltof the title compound. LCMS calculated for C₂₃H₁₈F₂N₇O₂ (M+H)⁺:m/z=462.2; Found: 462.2.

Example 14.N-(7-Fluoro-1-methyl-4-o-tolyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(7-Fluoro-2-methyl-4-o-tolyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. A mixture ofN-(4-Bromo-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(4-bromo-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution of 4-bromo-7-fluoro-1-methyl-5-nitro-1H-indazole and4-bromo-7-fluoro-2-methyl-5-nitro-2H-indazole (from Example 1, Step 2;257 mg, 0.938 mmol) in a 1:1:1 mixture of THF/MeOH/Water (4 mL) wastreated with iron (209 mg, 3.75 mmol) and ammonium chloride (301 mg,5.63 mmol). The reaction mixture was stirred at 80° C. for 1 hr. Themixture was then diluted with ethyl acetate and filtered through a padof Celite. The filtrate was washed with water and brine, dried oversodium sulfate and filtered. The resulting residue was treated with2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (256 mg, 1.032mmol), HATU (428 mg, 1.125 mmol), DMF (4689 μL) and Hunig's base (328μL, 1.876 mmol). The reaction mixture was stirred at room temperaturefor 30 min. Water was then added and the resulting solid was collectedby filtration, washed with water and hexane, and air dried. The crudeproduct was used in the next step without further purification (303 mg,68%). This compound was isolated as a 1:1 mixture of regioisomers aroundthe indazole. Peak 1: LCMS calculated for C₂₀H₁₅BrF₂N₅O₂ (M+H)⁺:m/z=474.0/476.0; Found: 474.0/476.0. Peak 2: LCMS calculated forC₂₀H₁₅BrF₂N₅O₂ (M+H)⁺: m/z=474.0/476.0; Found: 474.0/476.0.

Step 2:N-(7-Fluoro-1-methyl-4-o-tolyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(7-Fluoro-2-methyl-4-o-tolyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture ofN-(4-bromo-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(4-bromo-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(15 mg, 0.032 mmol), o-tolylboronic (6 mg, 0.047 mmol), XPhos Pd G2 (2.5mg, 3.16 μmol) and potassium phosphate, tribasic (13.4 mg, 0.063 mmol)were combined with 1,4-dioxane (253 μL) and water (63.3 μL). Thereaction flask was evacuated, back filled with nitrogen, and thenstirred at 90° C. for 1 h. The mixture was diluted with acetonitrile,filtered and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to provide TFA salts of the title compounds. Peak 1: LCMScalculated for C₂₇H₂₂F₂N₅O₂ (M+H)⁺: m/z=486.2; Found: 486.2. Peak 2:LCMS calculated for C₂₇H₂₂F₂N₅O₂ (M+H)⁺: m/z=486.2; Found: 486.2.

Example 15.(R)—N-(4-(3-aminopiperidin-1-yl)-7-cyano-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideand(R)—N-(4-(3-aminopiperidin-1-yl)-7-cyano-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (R)-tert-butyl1-(5-nitro-1H-indazol-4-yl)piperidin-3-ylcarbamate

A solution of 4-bromo-5-nitro-1H-indazole (100 mg, 0.413 mmol) andtert-butyl (R)-piperidin-3-ylcarbamate (124 mg, 0.620 mmol) in DMSO(1377 μL) was treated with Hunig's base (144 μL, 0.826 mmol). Thereaction mixture was heated to 90° C. for 2 hrs, then cooled to roomtemperature, quenched with water and extracted with ethyl acetate. Thecombined organic phases were washed with water and brine, dried oversodium sulfate and concentrated. The crude product was used in the nextstep without further purification. LCMS calculated for C₁₇H₂₄N₅O₄(M+H)⁺: m/z=362.2; Found: 362.2.

Step 2. A mixture of (R)-tert-butyl1-(7-iodo-1-methyl-5-nitro-1H-indazol-4-yl)piperidin-3-ylcarbamate and(R)-tert-butyl1-(7-iodo-2-methyl-5-nitro-2H-indazol-4-yl)piperidin-3-ylcarbamate

A solution of tert-butyl(R)-(1-(5-nitro-1H-indazol-4-yl)piperidin-3-yl)carbamate (450 mg, 1.245mmol) in DMF (6300 μL) was treated with NIS (280 mg, 1.245 mmol) and thereaction mixture was stirred at room temperature for 1 h. Then potassiumcarbonate (344 mg, 2.5 mmol) and methyl iodide (171 μL, 2.74 mmol) wereadded and the mixture was heated to 80° C. for 1 h. The reaction mixturewas treated with water and extracted with ethyl acetate. The combinedorganic phases were washed with water and brine, dried over sodiumsulfate and concentrated. The residue was purified by Biotage Isolera™(flash purification system with ethyl acetate/hexane at a ratio from 30to 100%) to provide the desired product as an orange solid (503 mg,81%). Peak 1: LCMS calculated for C₁₈H₂₅IN₅O₄ (M+H)⁺: m/z=502.2; Found:502.2. Peak 2: LCMS calculated for C₁₈H₂₅IN₅O₄ (M+H)⁺: m/z=502.2; Found:502.2.

Step 3. A mixture of (R)-tert-butyl1-(5-amino-7-iodo-1-methyl-1H-indazol-4-yl)piperidin-3-ylcarbamate and(R)-tert-butyl1-(5-amino-7-iodo-2-methyl-2H-indazol-4-yl)piperidin-3-ylcarbamate

A solution of tert-butyl(R)-(1-(3-iodo-1-methyl-5-nitro-1H-indazol-4-yl)piperidin-3-yl)carbamateand tert-butyl(R)-(1-(3-iodo-2-methyl-5-nitro-2H-indazol-4-yl)piperidin-3-yl)carbamate(475 mg, 0.947 mmol) in a 1:1:1 (v/v/v) mixture of MeOH/THF/Water (4.5mL) was treated with iron (212 mg, 3.79 mmol) and ammonium chloride (304mg, 5.68 mmol). The mixture was heated to 65° C. for 2 hrs, diluted withmethanol and filtered through a pad of Celite. The filtrate wasconcentrated, partitioned between ethyl acetate and water and the phaseswere separated. The organic phase was washed with brine, dried oversodium sulfate and concentrated. The crude product was purified byBiotage Isolera™ (flash purification system with ethyl acetate/hexane ata ratio from 30 to 100%) to provide the desired product as a brown solid(261 mg, 58%). Peak 1: LCMS calculated for C₁₈H₂₇IN₅O₂ (M+H)⁺:m/z=472.2; Found: 472.2. Peak 2: LCMS calculated for C₁₈H₂₇IN₅O₂ (M+H)⁺:m/z=472.2; Found: 472.2.

Step 4. A mixture of (R)-tert-butyl1-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-iodo-1-methyl-1H-indazol-4-yl)piperidin-3-ylcarbamateand (R)-tert-butyl1-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-iodo-2-methyl-2H-indazol-4-yl)piperidin-3-ylcarbamate

A solution of 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(151 mg, 0.609 mmol), a mixture of ter t-butyl(R)-(1-(5-amino-3-iodo-1-methyl-1H-indazol-4-yl)piperidin-3-yl)carbamateand ter t-butyl(R)-(1-(5-amino-3-iodo-2-methyl-2H-indazol-4-yl)piperidin-3-yl)carbamate(261 mg, 0.554 mmol) and HATU (253 mg, 0.664 mmol) in DMF (2769 μL) wastreated with Hunig's base (193 μL, 1.107 mmol). The reaction mixture wasstirred at room temperature for 1 h, then treated with water andextracted with dichloromethane. The combined organic phases were washedwith water and brine, dried over sodium sulfate and concentrated.

The residue was purified by Biotage Isolera™ (flash purification systemwith methanol/dichloromethane at a ratio from 2 to 10%) to provide thedesired product (250 mg, 64%) as a 1:1 mixture of indazole regioisomers.Peak 1: LCMS calculated for C₃₀H₃₄FIN₇O₄ (M+H)⁺: m/z=702.2; Found:702.2. Peak 2: LCMS calculated for C₃₀H₃₄FIN₇O₄ (M+H)⁺: m/z=702.2;Found: 702.2.

Step 5:(R)—N-(4-(3-aminopiperidin-1-yl)-7-cyano-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideand(R)—N-(4-(3-aminopiperidin-1-yl)-7-cyano-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of (R)-tert-butyl1-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-iodo-1-methyl-1H-indazol-4-yl)piperidin-3-ylcarbamateand (R)-tert-butyl1-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-iodo-2-methyl-2H-indazol-4-yl)piperidin-3-ylcarbamate(37 mg, 0.053 mmol), tetrakis(triphenylphosphine)palladium(O) (6.1 mg,5.27 μmop and zinc cyanide (12.4 mg, 0.105 mmol) was combined with DMF(264 μL). The reaction flask was evacuated, back filled with nitrogen,then stirred at 100° C. overnight. The mixture was cooled to roomtemperature, treated with water and extracted with ethyl acetate. Thecombined organic phases were washed with water and brine, dried oversodium sulfate and concentrated. To the residue was added TFA. Afterstirring for 30 mins at room temperature, the mixture was diluted withmethanol and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to provide TFA salts of the title compounds. Peak 1: LCMScalculated for C₂₆H₂₆FN₈₀₂ (M+H)⁺: m/z=501.2; Found: 501.2. Peak 2: LCMScalculated for C₂₆H₂₆FN₈₀₂ (M+H)⁺: m/z=501.2; Found: 501.2.

Example 16.(R)-4-(3-aminopiperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-N,1-dimethyl-1H-indazole-7-carboxamideand(R)-4-(3-aminopiperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-N,2-dimethyl-2H-indazole-7-carboxamide

Step 1. A mixture of(R)-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-1-methyl-1H-indazole-7-carboxylicacid and(R)-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-2-methyl-2H-indazole-7-carboxylicacid

A mixture of (R)-tert-butyl1-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-iodo-1-methyl-1H-indazol-4-yl)piperidin-3-ylcarbamateand (R)-tert-butyl1-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-iodo-2-methyl-2H-indazol-4-yl)piperidin-3-ylcarbamate(Example 15, Step 4; 285 mg, 0.406 mmol), dppf-PdCl₂ (33.2 mg, 0.041mmol) and triethylamine (170 μL, 1.219 mmol) were combined with DMF(2437 μL) and MeOH (1625 μl). The reaction flask was evacuated, backfilled with carbon monoxide from a balloon, and then stirred at 80° C.for 2 h. After cooling, water and ethyl acetate were added and thephases were separated. The aqueous phase was extracted with ethylacetate and the combined organic phases were washed with water andbrine, dried over sodium sulfate and concentrated. The residue waspurified by Biotage Isolera™ (flash purification system with ethylacetate/hexane at a ratio from 0 to 100%) to provide the desiredproduct.

To the residue was added a 1:1:1 (v/v/v) mixture of THF/MeOH/Water (1.5mL) followed by lithium hydroxide (83 mg, 2.031 mmol). The reactionmixture was stirred at room temperature overnight, and thenconcentrated. The residue was acidified with 1 N HCl, and extracted withethyl acetate. The combined organic phases were washed with brine, driedover sodium sulfate and concentrated. The crude solid was used in thenext step without further purification. LCMS calculated for C₃₁H₃₅FN₇O₆(M+H)⁺: m/z=620.2; Found: 620.2.

Step 2.(R)-4-(3-aminopiperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-N,1-dimethyl-1H-indazole-7-carboxamideand(R)-4-(3-aminopiperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-N,2-dimethyl-2H-indazole-7-carboxamide

A solution of(R)-4-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-1-methyl-1H-indazole-7-carboxylicacid and(R)-4-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-2-methyl-2H-indazole-7-carboxylicacid (15 mg, 0.024 mmol) and HATU (11 mg, 0.029 mmol) in DMF (242 μl)was treated with methanamine (36.3 μL, 0.073 mmol) and Hunig's base(12.7 μL, 0.073 mmol). The reaction mixture was stirred at roomtemperature for 30 mins, then treated with water and extracted withethyl acetate. The combined organic phases were washed with brine, driedover sodium sulfate and concentrated. TFA (1 mL) was added to theresidue and the reaction mixture was stirred at room temperature for 30min, diluted with methanol and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min) to provide TFA salts of the titlecompounds. Peak 1: LCMS calculated for C₂₇H₃₀FN₈O₃ (M+H)⁺: m/z=533.2;Found: 533.2. Peak 2: LCMS calculated for C₂₇H₃₀FN₈O₃ (M+H)⁺: m/z=533.2;Found: 533.2.

Example 17.(R)—N-(4-(3-Aminopyrrolidin-1-yl)-7-fluoro-1-(2-hydroxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1.4-Bromo-1-(2-(tert-butyldimethylsilyloxy)ethyl)-7-fluoro-5-nitro-1H-indazole

A solution of 4-bromo-7-fluoro-5-nitro-1H-indazole (from Example 1, Step1; 375 mg, 1.44 mmol) in DMF (7200 μL) was treated with potassiumcarbonate (399 mg, 2.88 mmol) and(2-bromoethoxy)(tert-butyl)dimethylsilane (308 μl, 1.442 mmol). Thereaction mixture was heated to 90° C. for 2 h. The mixture was thencooled to room temperature, treated with water and extracted with ethylacetate. The combined organic phases were washed with water and brine,dried over sodium sulfate and concentrated. The residue was purified byBiotage Isolera™ (flash purification system with ethyl acetate/hexane ata ratio from 0 to 50%) to provide the desired product as a yellow solid(151 mg, 25%). LCMS calculated for C₁₅H₂₂BrFN₃O₃Si (M+H)⁺:m/z=418.0/420.0; Found: 418.0/420.0.

Step 2. (R)-tert-butyl1-(5-amino-1-(2-(tert-butyldimethylsilyloxy)ethyl)-7-fluoro-1H-indazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-fluoro-5-nitro-1H-indazole(50 mg, 0.120 mmol), tert-butyl (R)-pyrrolidin-3-ylcarbamate (33.4 mg,0.179 mmol), Ruphos Pd G2 (9.28 mg, 0.012 mmol) and cesium carbonate (78mg, 0.239 mmol) was combined with 1,4-dioxane (400 μL) and the reactionflask was evacuated, back filled with nitrogen, then stirred at 60° C.for 1 h. The mixture was diluted with dichloromethane, filtered througha pad of Celite and concentrated.

The intermediate residue was dissolved in a 1:1:1 (v/v/v) mixture ofMeOH/THF/water and treated with iron (26.7 mg, 0.478 mmol) and ammoniumchloride (38.4 mg, 0.717 mmol). The reaction mixture was stirred at 80°C. for 1 h, diluted with ethyl acetate and filtered through a pad ofCelite. The filtrate was washed with water and brine, dried over sodiumsulfate and concentrated. The crude product was used in the next stepwithout further purification. LCMS calculated for C₂₄H₄₁FN₅O₃Si (M+H)⁺:m/z=494.2; Found: 494.2.

Step 3.(R)—N-(4-(3-aminopyrrolidin-1-yl)-7-fluoro-1-(2-hydroxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(32.7 mg, 0.132 mmol), tert-butyl(R)-(1-(5-amino-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-fluoro-1H-indazol-4-yl)pyrrolidin-3-yl)carbamate(65 mg, 0.132 mmol) and HATU (60.1 mg, 0.158 mmol) in DMF (1317 μl) wastreated with Hunig's base (46.0 μl, 0.263 mmol). The reaction mixturewas stirred at room temperature for 30 min, treated with water andfiltered. The resultant precipitate was washed with water and hexane,and air dried. The solid was then dissolved in a 1:1 mixture of MeOH/4Nsolution of HCl in dioxane (1 mL), stirred at room temperature for 30min, and then diluted with methanol and purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to provide the TFA salt of thetitle compound. LCMS calculated for C₂₅H₂₆F₂N₇O₃ (M+H)⁺: m/z=510.2;Found: 510.2.

Example 18.N-(1,7-Dimethyl-4-(piperazin-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(2,7-dimethyl-4-(piperazin-1-yl)-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-butyl 4-(5-nitro-1H-indazol-4-yl)piperazine-1-carboxylate

This compound was prepared in an analogous fashion to Example 15, Step1, using N-Boc piperidine instead of (R)-3-amino piperidine as thecoupling partner. LCMS calculated for C₁₆H₂₂N₅O₄ (M+H)⁺: m/z=348.2;Found: 348.2.

Step 2. A mixture of tert-butyl4-(7-iodo-1-methyl-5-nitro-1H-indazol-4-yl)piperazine-1-carboxylate andtert-butyl4-(7-iodo-2-methyl-5-nitro-2H-indazol-4-yl)piperazine-1-carboxylate

A solution of tert-butyl4-(5-nitro-1H-indazol-4-yl)piperazine-1-carboxylate (373 mg, 1.074 mmol)in DMF (3579 μL) was treated with NIS (242 mg, 1.074 mmol) and thereaction mixture was stirred at room temperature overnight. Then,potassium carbonate (297 mg, 2.148 mmol) and methyl iodide (101 μL,1.611 mmol) were added and the reaction mixture was heated to 80° C. for1 h. The reaction mixture was then cooled to room temperature, treatedwith water, and then extracted with ethyl acetate. The combined organicphases were washed with water and brine, dried over sodium sulfate, andconcentrated. The crude product was then purified by Biotage Isolera™(flash purification system with ethyl acetate/hexane at a ratio from 0to 100%) to provide the desired product (358 mg, 68%). Peak 1: LCMScalculated for C₁₇H₂₃IN₅O₄ (M+H)⁺: m/z=488.2; Found: 488.2. Peak 2: LCMScalculated for C₁₇H₂₃IN₅O₄ (M+H)⁺: m/z=488.2; Found: 488.2.

Step 3. A Mixture of tert-butyl4-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-iodo-1-methyl-1H-indazol-4-yl)piperazine-1-carboxylateand tert-butyl4-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-iodo-2-methyl-2H-indazol-4-yl)piperazine-1-carboxylate

A solution of tert-butyl4-(7-iodo-1-methyl-5-nitro-1H-indazol-4-yl)piperazine-1-carboxylate andtert-butyl4-(7-iodo-2-methyl-5-nitro-2H-indazol-4-yl)piperazine-1-carboxylate (358mg, 0.735 mmol) in a 1:1:1 (v/v/v) mixture of Water/THF/MeOH (3 mL) weretreated with iron (164 mg, 2.94 mmol) and ammonium chloride (236 mg,4.41 mmol). The mixture was heated to 80° C. for 1 h, then diluted withethyl acetate and filtered through a pad of Celite. The filtrate waspartitioned between ethyl acetate and water and the phases wereseparated. The organic phase was washed with water and brine, dried oversodium sulfate and concentrated.

The resultant residue was combined with2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (201 mg, 0.808mmol), HATU (335 mg, 0.882 mmol) and DMF (3 mL), and treated withHunig's base (385 μL, 2.2 mmol). After stirring at room temperature for30 min, water was added and the resulting precipitate was collected byfiltration, washed with water and hexane, and then air dried overnight.The crude solid was used in the next step without further purification.Peak 1: LCMS calculated for C₂₉H₃₂FIN₇O₄ (M+H)⁺: m/z=688.2; Found:688.2. Peak 2: LCMS calculated for C₂₉H₃₂FIN₇O₄ (M+H)⁺: m/z=688.2;Found: 688.2.

Step 4.N-(1,7-dimethyl-4-(piperazin-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(2,7-dimethyl-4-(piperazin-1-yl)-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl4-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-iodo-1-methyl-1H-indazol-4-yl)piperazine-1-carboxylateand tert-butyl4-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-iodo-2-methyl-2H-indazol-4-yl)piperazine-1-carboxylate(200 mg, 0.291 mmol), trimethylboroxine (81 μL, 0.582 mmol), dppf-PdCl₂(23.76 mg, 0.029 mmol) and potassium phosphate, tribasic (123 mg, 0.582mmol) were combined with 1,4-dioxane (2300 μL) and water (582 μL). Thereaction flask was evacuated, back filled with nitrogen, and stirred at80° C. overnight. The mixture was diluted with dichloromethane andfiltered through a pad of Celite. The filtrate was concentrated,dissolved in TFA and stirred at room temperature for 30 min. The mixturewas added dropwise to a solution of saturated aqueous sodiumbicarbonate. After bubbling subsided, the mixture was extracted withdichloromethane. The combined organic phases were washed with saturatedaqueous sodium bicarbonate and brine, dried over sodium sulfate, andconcentrated. The residue was dissolved in methanol and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide TFA salts of the title compounds. Peak 1: LCMS calculated forC₂₅H₂₇FN₇O₂ (M+H)⁺: m/z=476.2; Found: 476.2. Peak 2: LCMS calculated forC₂₅H₂₇FN₇O₂ (M+H)⁺: m/z=476.2; Found: 476.2.

Example 19.(R)—N-(4-(3-aminopyrrolidin-1-yl)-1,7-dimethyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 18 (and detailed below), using(R)-tert-butyl pyrrolidin-3-ylcarbamate instead of N-Boc piperidine asstarting material.

Step 1. tert-Butyl(R)-(1-(7-iodo-2-methyl-5-nitro-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate

A solution of 4-bromo-5-nitro-1H-indazole (1.0 g, 4.13 mmol) and tert-butyl (R)-(0.770 g, 4.13 mmol) in DMSO (13.77 ml) was treated withHunig's base (1.443 mL, 8.26 mmol) and the reaction mixture was heatedto 90° C. for 1 hr. The reaction mixture was cooled, treated with waterand extracted with ethyl acetate. The organic phase was washed withwater and brine, dried over sodium sulfate and concentrated. The crudeproduct was dissolved in DMF (12 mL) and NIS (0.930 g, 4.13 mmol) wasadded. The reaction mixture was stirred at r.t. overnight, then quenchedwith water and extracted with ethyl acetate. The organic phase waswashed with water and brine, dried over sodium sulfate and concentrated.The crude product was dissolved in DMF (25 mL) and treated withpotassium carbonate (0.857 g, 6.20 mmol) and methyl iodide (0.310 mL,4.96 mmol). The reaction mixture was heated to 70° C. for 3 hr, thentreated with water and extracted with ethyl acetate. The organic phasewas washed with water and brine, dried over sodium sulfate andconcentrated. The crude product was purified by Biotage Isolera™(20-100% ethyl acetate in hexanes) to provide the desired 2H isomer as ared solid (840 mg, 42%). LCMS calculated for C₁₇H₂₃IN₅O₄ (M+H)⁺:m/z=488.2; Found: 488.2.

Step 2. tert-Butyl(R)-(1-(2,7-dimethyl-5-nitro-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate

A mixture of ter t-butyl(R)-(1-(7-iodo-2-methyl-5-nitro-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate(839 mg, 1.72 mmol), DPPF-PdCl₂ (141 mg, 0.172 mmol), potassiumcarbonate (476 mg, 3.44 mmol) and trimethylboroxine (361 μl, 2.58 mmol)in 1,4-dioxane (5 ml) and water (1 ml) was degassed by evacuation andback filling with nitrogen. The mixture was heated to 100° C. overnight.The mixture was diluted with DCM and filtered through a plug of Celite.The filtrate was concentrated and the residue purified by BiotageIsolera™ (40-100% ethyl acetate in hexanes) to provide the desiredproduct as a red solid (384 mg, 59%). LCMS calculated for C₁₈H₂₆N₅O₄(M+H)⁺: m/z=376.2; Found: 376.2.

Step 3. tert-Butyl(R)-(1-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-2,7-dimethyl-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate

A solution of ter t-butyl(R)-(1-(2,7-dimethyl-5-nitro-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate(384 mg, 1.023 mmol) in a 1:1:1 mixture of THF/MeOH/water (6 mL) wastreated with iron (228 mg, 4.09 mmol) and ammonium chloride (328 mg,6.14 mmol). The reaction mixture was heated to 60° C. for 1 hr, thendiluted with ethyl acetate and filtered through a plug of Celite. Thefiltrate was washed with water and brine, dried over sodium sulfate andconcentrated. The crude product was dissolved in DMF (5114 μl) and2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (254 mg, 1.023mmol) (from Example 1, Step 3), HATU (428 mg, 1.125 mmol) and Hunig'sbase (357 μL, 2.05 mmol) were added. The reaction mixture was stirred atr.t. for 30 mins, then quenched with water and extracted with ethylacetate. The organic phase was washed with water and brine, dried oversodium sulfate and concentrated. The crude product was purified byBiotage Isolera™ (50-100% ethyl acetate in hexanes) to provide thedesired product (416 mg, 71%). LCMS calculated for C₃₀H₃₅FN₇O₄ (M+H)⁺:m/z=576.2; Found: 576.2.

Step 4.(R)—N-(4-(3-Aminopyrrolidin-1-yl)-1,7-dimethyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Tert-butyl(R)-(1-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-2,7-dimethyl-2H-indazol-4-yl)pyrrolidin-3-yl)carbamate(416 mg, 1.02 mmol) was treated with TFA (3 mL) and the reaction mixturewas stirred at r.t. for 30 mins. The reaction mixture was diluted withmethanol and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to provide TFA salt of the title compound. LCMS calculated forC₂₅H₂₇FN₇O₂ (M+H)⁺: m/z=476.2; Found: 476.2. ¹H NMR (500 MHz, DMSO) δ10.79 (s, 1H), 9.26 (d, J=5.0 Hz, 1H), 8.50 (s, 1H), 8.13 (d, J=5.0 Hz,1H), 8.04 (s, 2H), 7.86 (s, 1H), 7.57 (q, J=8.3 Hz, 1H), 7.08 (d, J=8.4Hz, 1H), 7.02 (t, J=8.7 Hz, 1H), 4.18 (s, 3H), 3.79 (s, 4H), 3.64 (s,1H), 3.58-3.54 (m, 1H), 3.51 (q, J=8.3 Hz, 1H), 3.20 (ddd, J=18.0, 9.1,5.2 Hz, 2H), 2.49 (s, 3H), 2.13-2.01 (m, 1H), 1.90 (ddt, J=11.3, 6.9,3.4 Hz, 1H).

Example 20.N-(7-Fluoro-1-methyl-4-(pyridin-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 14, using pyridin-3-ylboronic acidinstead of o-tolylboronic acid as starting material. LCMS calculated forC₂₅H₁₉F₂N₆O₆ (M+H)⁺: m/z=473.2; Found: 473.2.

Example 21.N-(7-Fluoro-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 14, using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of o-tolylboronic acid as starting material. LCMS calculated forC₂₄H₂₀F₂N₇O₂ (M+H)⁺: m/z=476.2; Found: 476.2.

Example 22.N-(7-Fluoro-4-(3-(hydroxymethyl)phenyl)-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 14, using 3-(hydroxymethyl)phenylboronicacid instead of o-tolylboronic acid as starting material. LCMScalculated for C₂₇H₂₂F₂N₅O₃ (M+H)⁺: m/z=502.2; Found: 502.2.

Example 23.N-(7-Fluoro-4-(2-(hydroxymethyl)phenyl)-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 14, using 2-(hydroxymethyl)phenylboronicacid instead of o-tolylboronic acid as starting material. LCMScalculated for C₂₇H₂₂F₂N₅O₃ (M+H)⁺: m/z=502.2; Found: 502.2.

Example 24.N-(4-(3-((Dimethylamino)methyl)phenyl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 14, usingN,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamineinstead of o-tolylboronic acid as starting material. LCMS calculated forC₂₉H₂₇F₂N₆O₆ (M+H)⁺: m/z=529.2; Found: 529.2.

Example 25.N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-(2-hydroxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 17, using(1S,4S)-2,5-diazabicyclo[2.2.1]heptane instead of tert-butyl(R)-pyrrolidin-3-ylcarbamate as starting material. LCMS calculated forC₂₆H₂₆F₂N₇O₃ (M+H)⁺: m/z=522.2; Found: 522.2.

Example 26.N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Examples 17 and 25, using1-bromo-2-methoxyethane instead of(2-bromoethoxy)(tert-butyl)dimethylsilane as starting material. LCMScalculated for C₂₇H₂₈F₂N₇O₃ (M+H)⁺: m/z=536.2; Found: 536.3. 1H NMR (500MHz, DMSO-d6) δ 10.45 (s, 1H), 9.27 (d, J=5.0 Hz, 1H), 8.39 (d, J=1.9Hz, 1H), 8.15 (d, J=5.0 Hz, 1H), 7.67 (d, J=12.8 Hz, 1H), 7.56 (q, J=8.4Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 7.00 (t, J=8.8 Hz, 1H), 4.63 (t, J=5.2Hz, 2H), 4.56-4.49 (m, 1H), 4.45-4.37 (m, 1H), 3.83-3.79 (m, 2H), 3.78(s, 3H), 3.75 (t, J=5.2 Hz, 2H), 3.51 (d, J=10.8 Hz, 2H), 3.38-3.31 (m,1H), 3.27-3.22 (m, 1H), 3.20 (s, 3H), 2.06 (d, J=10.3 Hz, 1H), 1.79 (d,J=10.4 Hz, 1H) ppm.

Example 27.N-(4-(4-(Dimethylamino)piperidin-1-yl)-3-iodo-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. 4-Bromo-3-iodo-5-nitro-1H-indazole

NIS (1.4 g, 6.32 mmol) was added to a solution of4-bromo-5-nitro-1H-indazole (1.5 g, 6.20 mmol) in DMF (15 mL). Thereaction mixture was stirred at 70° C. for 2 h, cooled to roomtemperature, treated with water, and the product was collected byfiltration. The solid was washed with water and air dried. LCMScalculated for C₇H₄BrIN₃O₂ (M+H)⁺: m/z=367.9; Found: 367.8.

Step 2. 4-Bromo-3-iodo-1-methyl-5-nitro-1H-indazole

NaH (0.288 g, 7.20 mmol, 60% in mineral oil) was added to a solution of4-bromo-3-iodo-5-nitro-1H-indazole (2.12 g, 5.76 mmol) and iodomethane(0.721 mL, 11.52 mmol) in DMF (14 mL). The reaction mixture was stirredat room temperature for 1 h, treated with water and the precipitatedproduct was collected by filtration. The solid was washed with water andair dried. LCMS calculated for C₈H₆BrIN₃O₂ (M+H)⁺: m/z=381.9; Found:381.9.

Step 3.1-(3-Iodo-1-methyl-5-nitro-1H-indazol-4-yl)-N,N-dimethylpiperidin-4-amine

A solution of 4-bromo-3-iodo-1-methyl-5-nitro-1H-indazole (2.1 g, 5.50mmol) and N,N-dimethylpiperidin-4-amine (1.057 g, 8.25 mmol) in DMSO (18mL) was treated with triethylamine (1.150 mL, 8.25 mmol). The reactionmixture was heated to 80° C. for 1 h. After cooling to room temperature,the reaction mixture was diluted with dichloromethane, washed withbrine, dried over sodium sulfate, and concentrated. The crude productwas used in the next step without further purification. LCMS calculatedfor C₁₅H₂₁IN₅O₂ (M+H)⁺: m/z=430.1; Found: 430.2.

Step 4.4-(4-(Dimethylamino)piperidin-1-yl)-3-iodo-1-methyl-1H-indazol-5-amine

A mixture of1-(3-iodo-1-methyl-5-nitro-1H-indazol-4-yl)-N,N-dimethylpiperidin-4-amine(2.36 g, 5.50 mmol), iron (1.53 g, 27.5 mmol) and ammonium chloride(1.76 g, 33.0 mmol) in THF (5 mL), water (5 mL) and methanol (5 mL) wasstirred at 60° C. for 3 h. After cooling to room temperature, themixture was filtered through a pad of Celite and diluted withdichloromethane. The organic phase was separated, washed with brine,dried over sodium sulfate, and concentrated. The crude product was usedin the next step without further purification. LCMS calculated forC₁₅H₂₃IN₅ (M+H)⁺: m/z=400.1; Found: 400.2.

Step 5.N-(4-(4-(Dimethylamino)piperidin-1-yl)-3-iodo-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (486 mg, 1.28 mmol) was added to a solution of4-(4-(dimethylamino)piperidin-1-yl)-3-iodo-1-methyl-1H-indazol-5-amine(340 mg, 0.852 mmol),2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (211 mg, 0.852mmol) and DIPEA (297 μL, 1.7 mmol) in DMF (5 mL). The reaction mixturewas stirred at room temperature for 30 min, then water was added, andthe precipitated product was collected by filtration. The solid waswashed with water, air dried, and then re-dissolved in a mixture ofacetonitrile and TFA and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to provide the TFA salt of the title compound.LCMS calculated for C₂₇H₃₀FIN₇O₂ (M+H)⁺: m/z=630.1; Found: 630.2.

Example 28.N-(4-(4-(Dimethylamino)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture ofN-(4-(4-(dimethylamino)piperidin-1-yl)-3-iodo-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Example 26, 10 mg, 0.016 mmol), trimethylboroxine (3.6 μl, 0.032 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(1.3 mg, 1.6 μmop and potassium phosphate, tribasic (6.7 mg, 0.032 mmol)was combined with 1,4-dioxane (1000 μl) and water (100 μl). The reactionflask was evacuated, back filled with nitrogen, and then stirred at 80°C. overnight. The reaction mixture was cooled to room temperature,filtered, diluted with CH₃CN and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min) to provide the TFA salt of the titlecompound. LCMS calculated for C₂₈H₃₃FN₇O₂ (M+H)⁺: m/z=518.2; Found:518.2.

Example 29.N-(4-(4-(Dimethylamino)piperidin-1-yl)-1-methyl-3-phenyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 27, using phenylboronic acid instead oftrimethylboroxine as starting material. LCMS calculated for C₃₃H₃₅FN₇O₂(M+H)⁺: m/z=580.3; Found: 580.3.

Example 30.N-(4-(4-(Dimethylamino)piperidin-1-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Example 27, using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of trimethylboroxine as starting material. LCMS calculated forC₃₁H₃₅FN₉O₂ (M+H)⁺: m/z=584.3; Found: 584.4.

Example 31.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. 4-Bromo-7-fluoro-1-(2-methoxyethyl)-5-nitro-1H-indazole

A mixture of 4-bromo-7-fluoro-5-nitro-1H-indazole (400 mg, 1.54 mmol)and cesium carbonate (1 g, 3.08 mmol) in DMF (8 ml) was treated with1-bromo-2-methoxyethane (217 μl, 2.31 mmol) and the reaction mixture washeated to 80° C. for 1 h. The mixture was then treated with water andthe product was extracted with ethyl acetate. The separated organicphase was washed with water and brine, dried over sodium sulfate andconcentrated. The crude product was purified by Biotage Isolera™ (flashpurification system with ethyl acetate/hexane at a ratio from 0 to 100%)to provide the desired product (110 mg, 23%). LCMS calculated forC₁₀H₁₀BrFN₃O₃ (M+H)⁺: m/z=318.0/320.0; found 318.0/320.0.

Step 2. tert-Butyl(3S,5S)-1-(5-amino-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

A solution of 4-bromo-7-fluoro-1-(2-methoxyethyl)-5-nitro-1H-indazole(36 mg, 0.113 mmol) and tert-butyl((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (29.4 mg, 0.136mmol) in DMSO (566 μl) was treated with triethylamine (31.5 μl, 0.226mmol) and the reaction mixture was heated to 90° C. for 1 h. The mixturewas then treated with water and the product was extracted with ethylacetate. The separated organic phase was washed with water and brine,dried over sodium sulfate and concentrated. The residue was dissolved ina 1:1:1 mixture of THF/MeOH/Water (1.5 mL) and treated with iron (25.3mg, 0.453 mmol) and ammonium chloride (36.3 mg, 0.679 mmol). The mixturewas heated to 60° C. for 1 h, then diluted with ethyl acetate andfiltered through a plug of Celite. The filtrate was washed with waterand brine, dried over sodium sulfate and concentrated. The crude productwas used in the next step without further purification. LCMS calculatedfor C₂₀H₃₁FN₅O₄ (M+H)⁺: m/z=424.2; found 424.2.

Step 3.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(11.72 mg, 0.047 mmol), HATU (21.55 mg, 0.057 mmol) and tert-butyl((3S,5S)-1-(5-amino-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(Step 2, 20 mg, 0.047 mmol) was treated with DMF (236 μl) and Hunig'sbase (16.50 μl, 0.094 mmol) and the reaction mixture stirred at roomtemperature for 30 mins. The mixture was then diluted with water and theresulting precipitate was collected by filtration and washed with waterand hexanes. The precipitate was dissolved in TFA (1.5 mL) and allowedto stand for 30 mins at room temperature. The solution was diluted withmethanol and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₇H₃₀F₂N₇O₄ (M+H)⁺: m/z=554.2; found554.2. ¹H NMR (500 MHz, DMSO) δ 10.72 (s, 1H), 9.26 (d, J=5.0 Hz, 1H),8.38 (s, 1H), 8.24 (d, J=13.6 Hz, 1H), 8.18 (d, J=5.0 Hz, 1H), 7.86 (s,2H), 7.63-7.48 (m, 1H), 7.05 (s, 1H), 7.00 (t, J=8.7 Hz, 1H), 5.33 (s,1H), 4.65 (t, J=5.2 Hz, 2H), 3.78 (d, J=7.5 Hz, 7H), 3.56 (dd, J=10.0,4.8 Hz, 1H), 3.36 (d, J=10.2 Hz, 1H), 3.22 (s, 3H), 3.18 (d, J=11.1 Hz,2H), 2.70-2.60 (m, 1H), 1.83 (d, J=16.4 Hz, 1H).

Example 32.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1.(R)-4-Bromo-7-fluoro-5-nitro-1-(tetrahydrofuran-3-yl)-1H-indazole

A solution of 4-bromo-7-fluoro-5-nitro-1H-indazole (300 mg, 1.15 mmol),(5)-tetrahydrofuran-3-ol (117 μl, 1.73 mmol) and triphenylphosphine (454mg, 1.731 mmol) in THF (5769 μl) was treated with DIAD (336 μl, 1.731mmol) dropwise and the reaction mixture was stirred at room temperatureovernight. The mixture was then concentrated and purified by BiotageIsolera™ (flash purification system with ethyl acetate/hexane at a ratiofrom 0 to 60%) to provide the desired product as a yellow solid (190 mg,50%). LCMS calculated for C₁₁H₁₀BrFN₃O₃ (M+H)⁺: m/z=330.0; Found: 330.0.

Step 2.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 31, steps 2 and 3 using(R)-4-bromo-7-fluoro-5-nitro-1-(tetrahydrofuran-3-yl)-1H-indazoleinstead of 4-bromo-7-fluoro-1-(2-methoxyethyl)-5-nitro-1H-indazole asstarting material. LCMS calculated for C₂₈H₃₀F₂N₇O₄ (M+H)⁺: m/z=566.2;Found: 566.2. ¹H NMR (500 MHz, DMSO) δ 10.74 (s, 1H), 9.27 (d, J=5.0 Hz,1H), 8.39 (d, J=1.9 Hz, 1H), 8.28 (d, J=13.7 Hz, 1H), 8.18 (d, J=5.0 Hz,1H), 7.85 (s, 3H), 7.63-7.47 (m, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.99 (t,J=8.7 Hz, 1H), 5.54 (s, 1H), 4.11 (dd, J=9.3, 6.3 Hz, 1H), 4.04 (q,J=7.6 Hz, 1H), 3.99 (dd, J=9.2, 3.5 Hz, 1H), 3.94-3.87 (m, 1H), 3.77 (s,5H), 3.56 (dd, J=10.0, 4.8 Hz, 1H), 3.35 (d, J=11.1 Hz, 1H), 3.18 (qd,J=10.9, 2.6 Hz, 2H), 2.67 (ddd, J=13.9, 9.5, 6.6 Hz, 1H), 2.46 (q, J=7.4Hz, 2H), 1.83 (d, J=13.6 Hz, 1H).

Example 33.(R)—N-(7-Fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 1, using (R)-tert-butyl2-(hydroxymethyl)piperazine-1-carboxylate instead of tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₅H₂₆F₂N₇O₃ (M+H)⁺: m/z=510.2; Found:510.2. ¹H NMR (600 MHz, DMSO) δ 11.07 (s, 1H), 9.47 (d, J=9.9 Hz, 1H),9.30 (d, J=4.9 Hz, 2H), 8.66 (s, 1H), 8.24 (s, 1H), 8.17 (d, J=4.9 Hz,1H), 7.57 (t, J=8.5 Hz, 1H), 7.09 (dd, J=8.4, 4.2 Hz, 2H), 5.43 (s, 1H),4.23 (s, 3H), 3.79 (s, 3H), 3.61 (dd, J=11.2, 4.2 Hz, 1H), 3.58-3.48 (m,3H), 3.47-3.38 (m, 1H), 3.33 (d, J=12.0 Hz, 1H), 3.13 (d, J=11.6 Hz,1H), 3.08-2.98 (m, 2H), 2.78 (d, J=10.2 Hz, 1H).

Example 34.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-1-(3-cyanopyridin-4-yl)-7-fluoro-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(3S,5S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-3-ylcarbamate

A solution of tert-butyl((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (1. g, 4.62 mmol)and tert-butyldimethylsilyl chloride (0.767 g, 5.09 mmol) in DCM (23 ml)was treated with triethylamine (0.967 ml, 6.94 mmol) and the reactionmixture was stirred at room temperature overnight. The reaction was thentreated with saturated sodium bicarbonate solution. The phases wereseparated and the aqueous phase was extracted with DCM. The combinedorganic phases were dried over sodium sulfate and concentrated. Theresulting yellow oil was used in the next step without furtherpurification (1.47 g, 96%). LCMS calculated for C₁₆H₃₅N₂O₃Si (M+H)⁺:m/z=331.2; Found: 331.2.

Step 2. tert-Butyl(3S,5S)-5-((tert-butyldimethylsilyloxy)methyl)-1-(7-fluoro-5-nitro-1H-indazol-4-yl)pyrrolidin-3-ylcarbamate

A solution of 4-bromo-7-fluoro-5-nitro-1H-indazole (330 mg, 1.269 mmol)and tert-butyl((3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)carbamate(503 mg, 1.523 mmol) in DMSO (5 ml) was treated with triethylamine (531μl, 3.81 mmol) and the reaction mixture was heated to 90° C. for 1 hr.The mixture was cooled, treated with water and the product was extractedwith ethyl acetate. The separated organic phase was washed with waterand brine, dried over sodium sulfate and concentrated. The crude productwas purified by Biotage Isolera™ (flash purification system with ethylacetate/hexane at a ratio from 0 to 100%) to provide the desired productas a solid (457 mg, 71%). LCMS calculated for C₂₃H₃₇FN₅O₅Si (M+H)⁺:m/z=510.2; Found: 510.2.

Step 3. tert-Butyl(3S,5S)-1-(5-amino-1-(3-cyanopyridin-4-yl)-7-fluoro-1H-indazol-4-yl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-3-ylcarbamate

A suspension of tert-butyl((3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(7-fluoro-5-nitro-1H-indazol-4-yl)pyrrolidin-3-yl)carbamate(50 mg, 0.098 mmol), 4-chloronicotinonitrile (27.2 mg, 0.196 mmol) inDMF (1 ml) was treated with sodium hydride (9.81 mg, 0.245 mmol) and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was then treated with water and the product extracted with ethylacetate. The separated organic phase was washed with water and brine,dried over sodium sulfate and concentrated. The crude product waspurified by Biotage Isolera™ (flash purification system with ethylacetate/hexane at a ratio from 0 to 100%) to provide the desiredintermediate as an orange oil. To this intermediate was added a 1:1:1mixture of THF/MeOH/water (1.5 mL), followed by iron (21.91 mg, 0.392mmol) and ammonium chloride (31.5 mg, 0.59 mmol). The mixture was heatedto 60° C. for 1 h, then diluted with ethyl acetate and filtered througha plug of Celite. The filtrate was washed with water and brine, driedover sodium sulfate and concentrated. The crude product was used in thenext step without further purification. LCMS calculated forC₂₉H₄₁FN₇O₃Si (M+H)⁺: m/z=582.2; Found: 582.2.

Step 4.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-1-(3-cyanopyridin-4-yl)-7-fluoro-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution of 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(15.90 mg, 0.064 mmol), HATU (29.8 mg, 0.078 mmol), tert-butyl(3S,5S)-1-(5-amino-1-(3-cyanopyridin-4-yl)-7-fluoro-1H-indazol-4-yl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-3-ylcarbamate(41 mg, 0.071 mmol) in DMF (356 μl) was treated with Hunig's base (24.87μl, 0.142 mmol) and the reaction mixture was stirred at room temperaturefor 30 mins. The reaction mixture was then treated with water and theproduct was extracted with ethyl acetate. The separated organic phasewas washed with water and brine, dried over sodium sulfate andconcentrated. The crude residue was dissolved in MeOH (0.5 mL) andtreated with 4N HCl in dioxane (0.5 mL). The mixture was stirred at roomtemperature for 30 mins, then diluted with MeOH and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₃₀H₂₆F₂N₉O₃ (M+H)⁺: m/z=598.2; Found: 598.2.

Example 35.N-(4-((2S,4S)-2-(Aminomethyl)-4-hydroxypyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (2S,4S)-tert-Butyl4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

A solution of (2S,4S)-1-tert-butyl 2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate (974 mg, 3.97 mmol) in DMF (20ml) was treated with imidazole (406 mg, 5.96 mmol), DMAP (48.5 mg, 0.397mmol) and TBS-Cl (718 mg, 4.77 mmol) and the reaction mixture wasstirred at room temperature for 3 h. The reaction mixture was thentreated with water and the product was extracted with ethyl acetate. Theseparated organic phase was washed with water and brine, dried oversodium sulfate and concentrated. The residue was dissolved in THF (40mL) and treated with lithium borohydride (2M in THF, 2.98 ml, 5.96 mmol)dropwise at 0° C. The reaction mixture was allowed to warm up to roomtemperature and was stirred overnight. The reaction mixture was treatedwith 1 N HCl solution, diluted with water and the product was extractedwith ethyl acetate. The separated organic phase was washed with waterand brine, dried over sodium sulfate and concentrated. The residue waspurified by CombiFlash™ (flash purification system with ethylacetate/hexane at a ratio from 0 to 50%) to provide the desired productas a pale yellow oil (700 mg, 52%). LCMS calculated for C₁₆H₃₄NO₄Si(M+H)⁺: m/z=332.2; Found: 332.2.

Step 2. (2S,4S)-tert-Butyl4-(tert-butyldimethylsilyloxy)-2-(0,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate

A solution of tert-butyl(2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(700 mg, 2.111 mmol), triphenylphosphine (831 mg, 3.17 mmol) andphthalimide (466 mg, 3.17 mmol) in THF (11 mL) was treated with DEAD(501 μL, 3.17 mmol) dropwise and the reaction mixture was stirred atroom temperature overnight. The reaction mixture was concentrated andpurified by CombiFlash™ (flash purification system with ethylacetate/hexane at a ratio from 0 to 100%) to provide the desired productas a pale yellow oil (500 mg, 51%). LCMS calculated for C₂₄H₃₇N₂O₅Si(M+H)⁺: m/z=461.2; Found: 461.2.

Step 3. (2S,4S)-tert-Butyl2-((benzyloxycarbonylamino)methyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-1-carboxylate

A solution of tert-butyl(2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-((1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate(497 mg, 1.079 mmol) in EtOH (11 mL) was treated with hydrazine hydrate(339 μl, 10.79 mmol) and the reaction mixture stirred at roomtemperature for 10 minutes, then at reflux for 30 mins. The mixture wasthen filtered through a plug of Celite and washed with ethanol. Thefiltrate was concentrated. The resultant residue was treated with DCM (3mL), Hunig's base (283 μl, 1.618 mmol) and benzyl chloroformate (185 μl,1.3 mmol). After stirring at room temperature for 30 mins, the mixturewas concentrated and purified by CombiFlash™ (flash purification systemwith ethyl acetate/hexane at a ratio from 0 to 100%) to provide thedesired product as a pale yellow oil (411 mg, 82%). LCMS calculated forC₂₄H₄₁N₂O₅Si (M+H)⁺: m/z=465.2; Found: 465.2.

Step 4. Benzyl((2S,4S)-1-(5-amino-7-fluoro-1-methyl-1H-indazol-4-yl)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-yl)methylcarbamate

A solution of tert-butyl(2S,4S)-2-((((benzyloxy)carbonyl)amino)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate(102 mg, 0.219 mmol) in MeOH (1 mL) was treated with 4N HCl in dioxane(1 mL) and the reaction mixture was stirred at room temperature for 2 h,then concentrated. The resultant residue was treated with DMSO (608 μl)and triethylamine (76 μl, 0.547 mmol) followed by4-bromo-7-fluoro-1-methyl-5-nitro-1H-indazole (50 mg, 0.182 mmol). Themixture was heated to 90° C. for 1 h. After cooling, the reaction wastreated with water and extracted with ethyl acetate. The separatedorganic phase was washed with water and brine, dried over sodium sulfateand concentrated. The residue was dissolved in a 1:1:1 mixture ofMeOH/THF/water (1.5 mL) and treated with iron (40.8 mg, 0.730 mmol) andammonium chloride (58.6 mg, 1.095 mmol). The mixture was heated to 60°C. for 1 h, then diluted with ethyl acetate and filtered through a plugof Celite. The filtrate was washed with water and brine, dried oversodium sulfate and concentrated. The crude product was used in the nextstep without further purification. LCMS calculated for C₂₇H₃₉FN₅O₃Si(M+H)⁺: m/z=528.2; Found: 528.2.

Step 5.N-(4-((2S,4S)-2-(aminomethyl)-4-hydroxypyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(36.0 mg, 0.145 mmol), HATU (66.2 mg, 0.174 mmol) and benzyl((2S,4S)-1-(5-amino-7-fluoro-1-methyl-1H-indazol-4-yl)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-yl)methylcarbamate(60 mg, 0.145 mmol) was treated with DMF (726 μl) and Hunig's base (50.7μl, 0.290 mmol) and the reaction mixture stirred at room temperature for30 mins. The reaction mixture was diluted with water and the resultingprecipitate was collected by filtration and washed with water andhexanes. The precipitate was treated with palladium on carbon (15 mg,0.03 mmol) and MeOH (1 mL). The reaction mixture was evacuated, backfilled with hydrogen gas from a balloon, then stirred at 60° C.overnight. The mixture was filtered through a plug of Celite andconcentrated. 4N HCl in dioxane (1 mL) was then added to the resultantresidue. After standing for 30 mins, the solution was diluted withmethanol and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to provide the desired product. LCMS calculated for C₂₅H₂₆F₂N₇O₃(M+H)⁺: m/z=510.2; Found: 510.2.

Example 36.N-(4-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-(2-fluoroethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The TFA salt of the title compound was prepared according to theprocedures described in Examples 17 and 25, using 1-bromo-2-fluoroethaneinstead of (2-bromoethoxy)(tert-butyl)dimethylsilane as startingmaterial. LCMS calculated for C₂₆H₂₅F₃N₇O₂ (M+H)+: m/z=524.2; Found:524.3. ¹H NMR (500 MHz, DMSO-d6) δ 10.53-10.37 (s, 1H), 9.30-9.13 (d,J=5.0 Hz, 1H), 9.13-9.00 (br, 1H), 8.48-8.34 (d, J=2.1 Hz, 1H),8.20-8.10 (d, J=5.0 Hz, 1H), 7.77-7.65 (d, J=12.8 Hz, 1H), 7.61-7.45(td, J=8.5, 6.9 Hz, 1H), 7.10-7.04 (d, J=8.5 Hz, 1H), 7.04-6.94 (m, 1H),4.90-4.84 (m, 1H), 4.84-4.81 (m, 1H), 4.79-4.72 (s, 2H), 4.56-4.49 (s,1H), 4.47-4.35 (s, 1H), 3.86-3.80 (s, 1H), 3.80-3.75 (s, 3H), 3.56-3.49(d, J=10.7 Hz, 1H), 3.41-3.31 (s, 1H), 3.29-3.16 (d, J=9.4 Hz, 1H),2.10-2.02 (d, J=10.7 Hz, 1H), 1.87-1.66 (d, J=10.6 Hz, 1H) ppm.

Example 37.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-(methoxy-d₃)-3-methylphenyl)pyrimidine-4-carboxamide

Step 1. 2-Fluoro-4-(methoxy-d₃)-1-methylbenzene

A solution of 3-fluoro-4-methylphenol (1.0 g, 7.93 mmol) in DMF (26.4ml) was treated with potassium carbonate (1.644 g, 11.89 mmol) andiodomethane-d₃ (0.592 ml, 9.51 mmol) and the reaction mixture heated to80° C. for 1 hr. The reaction Mixture was treated with water andextracted with diethyl ether. The organic phase was washed with waterand brine, dried over sodium sulfate and concentrated. The crude productwas used in the next step without further purification. LCMS calculatedfor C₈H₇D₃FO (M+H)⁺: m/z=144.2; Found: 144.2.

Step 2.2-(2-Fluoro-6-(methoxy-d₃)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of 2-fluoro-4-(methoxy-d₃)-1-methylbenzene (1.0 g, 6.98 mmol)and HMPA (1.823 ml, 10.48 mmol) in THF (35 ml) at −78° C. was treatedwith n-BuLi (2.5 M in hexanes, 3.35 ml, 8.38 mmol) dropwise and thereaction mixture was stirred at −78° C. for 1 hr. The mixture was thentreated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.166ml, 10.48 mmol) and the reaction mixture was stirred at −78° C. for 10mins, then warmed up to r.t. by removing the cooling bath. The reactionwas treated with aqueous 1N HCl and extracted with ethyl acetate. Theorganic phase was washed with water and brine, dried over sodium sulfateand concentrated. The crude product was used in the next step withoutfurther purification.

Step 3. Methyl2-(2-fluoro-6-(methoxy-d₃)-3-methylphenyl)pyrimidine-4-carboxylic acid

A solution of2-(2-fluoro-6-(methoxy-d₃)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1560 mg, 5.79 mmol) and Hunig's base (1012 μl, 5.79 mmol) in water (1.5ml) and 1,4-dioxane (12 mL) was treated with methyl2-chloropyrimidine-4-carboxylate (500 mg, 2.90 mmol) and ((t-Bu)₃P)₂Pd(74.0 mg, 0.145 mmol). The reaction flask was evacuated, back filledwith nitrogen, then stirred at 80° C. overnight. The reaction mixturewas then diluted with DCM and filtered through a plug of Celite. Thefiltrate was concentrated and the residue purified by Biotage Isolera™(0-100% ethyl acetate in hexanes) to provide the desired product. LCMScalculated for C₁₄H₁₁D₃FN₂O₃ (M+H)⁺: m/z=280.2; Found: 280.2.

Step 4.2-(2-Fluoro-6-(methoxy-d₃)-3-methylphenyl)pyrimidine-4-carboxylic acid

The crude product from the previous step was dissolved in a 1:1 mixtureof THF/water (4 mL). Lithium hydroxide (238 mg, 5.79 mmol) was added andthe reaction mixture was heated to 60° C. for 1 hr, then acidified to pH1 with 1 N HCl and extracted with ethyl acetate. The organic phase waswashed with brine, dried over sodium sulfate and concentrated. The crudeproduct was used in the next step without further purification. LCMScalculated for C₁₃H₉D₃FN₂O₃ (M+H)⁺: m/z=266.2; Found: 266.2.

Step 5.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-(methoxy-d₃)-3-methylphenyl)pyrimidine-4-carboxamide

A solution of2-(2-fluoro-6-(methoxy-d₃)-3-methylphenyl)pyrimidine-4-carboxylic acid(9.4 mg, 0.035 mmol), HATU (16 mg, 0.043 mmol) and tert-butyl((3S,5S)-1-(5-amino-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(Example 31, step 2, 15 mg, 0.035 mmol) in DMF (3504 μl) was treatedwith Hunig's base (12 μl, 0.071 mmol) and the reaction mixture allowedto stir at r.t. for 30 mins. The reaction mixture was treated with waterand extracted with ethyl acetate. The organic phase was washed withwater and brine, dried over sodium sulfate and concentrated. The crudeproduct was dissolved in TFA (1 mL) and allowed to stand at r.t. for 30mins, then diluted with MeOH and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₈H₂₉D₃F₂N₇O₄(M+H)⁺: m/z=571.2; Found: 571.2.

Example 38.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(4-amino-2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. 4-Bromo-3-fluoro-5-methoxyaniline

A solution of 3-fluoro-5-methoxyaniline (800 mg, 5.67 mmol) in DMF (20ml) was treated with NBS (1 g, 5.67 mmol) and the reaction mixturestirred at r.t. for 1 hr. The reaction mixture was treated with waterand ethyl acetate. The phases were separated and the aqueous phaseextracted with additional ethyl acetate. The combined organic phaseswere washed with water and brine, dried over sodium sulfate andconcentrated. The residue was purified by Biotage Isolera™ (10-50% ethylacetate in hexanes) to provide the desired product as an off white solid(1.05 g, 84%). LCMS calculated for C₇H₈BrFNO (M+H)⁺: m/z=220.0/222.0;Found: 220.0/222.0.

Step 2.3-Fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

A mixture of 4-bromo-3-fluoro-5-methoxyaniline (1.05 g, 4.77 mmol),bis-pin (1.82 g, 7.16 mmol), dppf-PdCl₂ (0.390 g, 0.477 mmol) andpotassium acetate (0.937 g, 9.54 mmol) in 1,4-dioxane (12 ml) wasdegassed by evacuation and back filling with nitrogen. The reactionmixture was stirred at 110° C. overnight. The reaction mixture wasdiluted with DCM and filtered through a plug of Celite. The filtrate wasconcentrated, then purified by Biotage Isolera™ (20-80% ethyl acetate inhexanes) to provide the desired product as a red oil. LCMS calculatedfor C₁₃H₂₀BFNO₃ (M+H)⁺: m/z=268.2; Found: 268.2.

Step 3. tert-Butyl((3S,5S)-1-(5-(2-chloropyrimidine-4-carboxamido)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A solution of 2-chloropyrimidine-4-carboxylic acid (70.4 mg, 0.444mmol), HATU (186 mg, 0.488 mmol) and tert-butyl((3S,5S)-1-(5-amino-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(188 mg, 0.444 mmol) in DMF (2 ml) was treated with Hunig's base (155μl, 0.888 mmol) and the reaction mixture allowed to stir at r.t. for 30mins. The reaction mixture was treated with water and extracted withethyl acetate. The organic phase was washed with water and brine, driedover sodium sulfate and concentrated. The crude product was purified byBiotage Isolera™ (40-100% ethyl acetate in hexanes) to provide thedesired product as an orange solid (207 mg, 83%). LCMS calculated forC₂₅H₃₂C₁FN₇₀₅ (M+H)⁺: m/z=564.2; Found: 564.2.

Step 4.N-(4-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(4-amino-2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl((3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-(2-chloropyrimidine-4-carboxamido)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)pyrrolidin-3-yl)carbamate(100 mg, 0.147 mmol),3-fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(59.1 mg, 0.221 mmol), XPhos Pd G2 (11.6 mg, 0.015 mmol) and Hunig'sbase (51.5 μl, 0.295 mmol) in water (300 μl) and 1,4-dioxane (1.2 ml)was evacuated, back filled with nitrogen and stirred at 90° C.overnight. The mixture was diluted with DCM and filtered through a plugof Celite. The filtrate was concentrated and the residue purified byBiotage (30-100% ethyl acetate in hexanes) to provide the desiredproduct as a brown powder. The residue was dissolved in a 1:1 mixture ofMeOH/4 N HCl in dioxane (1 mL) and heated to 80 degrees for 1 hr, thendiluted with MeOH and purified with prep-LCMS (XBridge C₁₈ column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₇H₃₁F₂N₈O₄ (M+H)⁺:m/z=569.2; Found: 569.2.

Example 39.N-(4-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxy-3-(methylcarbamoyl)phenyl)pyrimidine-4-carboxamide

Step 1. Methyl3-(4-((4-((2S,4S)-4-((tert-butoxycarbonyl)amino)-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)carbamoyl)pyrimidin-2-yl)-2-fluoro-4-methoxybenzoate

This compound was prepared similar to Example 37, using methyl2-fluoro-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-oxazaborolidin-2-yl)benzoateas the coupling partner. LCMS calculated for C₃₄H₄₀F₂N₇O₈ (M+H)⁺:m/z=712.2; Found: 712.2.

Step 2.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxy-3-(methylcarbamoyl)phenyl)pyrimidine-4-carboxamide

Methyl3-(4-((4-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)carbamoyl)pyrimidin-2-yl)-2-fluoro-4-methoxybenzoate(24 mg, 0.039 mmol) was dissolved in 1:1 THF/water (1 mL) and treatedwith LiOH (20 mg). After 30 mins at 60° C., the reaction mixture wastreated with 1N HCl and extracted with ethyl acetate. The organic phasewas dried and concentrated, then dissolved in DMF (0.5 mL) and treatedwith HATU (17.80 mg, 0.047 mmol), methanamine (39.0 μl, 0.078 mmol) andHunig's base (14 μl, 0.078 mmol). The reaction mixture was stirred atr.t. for 30 mins, treated with water and extracted with ethyl acetate.The organic phase was washed with water and brine, dried over sodiumsulfate and concentrated. The material was dissolved in a 1:1 mixture ofMeOH/4N HCl in dioxane (1 mL) and allowed to stir at 80° C. for 30 mins,then diluted with MeOH and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₉H₃₃F₂N₈O₅ (M+H)⁺:m/z=611.2; Found: 611.2.

Example 40.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl((3S,5S)-1-(5-(2-(3-chloro-2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

This compound was prepared according to Example 37, using2-(3-chloro-2-fluoro-6-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas the coupling partner. LCMS calculated for C₃₂H₃₇C₁F₂N₇O₆ (M+H)⁺:m/z=688.2; Found: 688.2.

Step 2.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrimidine-4-carboxamide

A solution of tert-butyl((3S,5S)-1-(5-(2-(3-chloro-2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(20 mg, 0.029 mmol), XPhos Pd G2 (2 mg, 2.91 μmol), potassium phosphate(12 mg, 0.058 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12mg, 0.058 mmol) in dioxane (200 μl) and water (48 μl) was evacuated,back filled with nitrogen, and then stirred at 90° C. for 1 hr. Thereaction mixture was diluted with DCM/water and the phases separated.The organic phase was concentrated, then redissolved in TFA (1 mL) andallowed to stand at r.t. for 30 mins. The mixture was then diluted withMeOH and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₃₁H₃₄F₂N₉O₄ (M+H)⁺: m/z=634.2; Found:634.2.

Example 41.(R)—N-(7-Fluoro-1-methyl-4-(methyl(piperidin-3-yl)amino)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 1, using tert-butyl (R)-3-(methylamino)piperidine-1-carboxylateinstead of tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as startingmaterial. LCMS calculated for C₂₆H₂₈F₂N₇O₂ (M+H)⁺: m/z=508.2; Found:508.2.

Example 42.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-6-(2-fluoro-6-methoxyphenyl)picolinamide

Step 1. tert-Butyl((3S,5S)-1-(5-amino-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)carbamate

This compound was prepared in an analogous fashion to Example 31, steps1-2, using tert-butyl((3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)carbamate(Example 34, Step 1) as starting material. LCMS calculated forC₂₆H₄₅FN₅O₄Si (M+H)⁺: m/z=538.2; Found: 538.2.

Step 2. tert Butyl((3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-(6-chloropicolinamido)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)pyrrolidin-3-yl)carbamate

This compound was prepared in an analogous fashion to Example 38, Step3, with 6-chloropicolinic acid used as the coupling partner. LCMScalculated for C₃₂H₄₇C₁FN₆O₅Si (M+H)⁺: m/z=677.2; Found: 677.2.

Step 3.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-6-(2-fluoro-6-methoxyphenyl)picolinamide

A solution of benzyl((3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5-(6-chloropicolinamido)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-4-yl)pyrrolidin-3-yl)carbamate(24 mg, 0.034 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (8.6 mg,0.051 mmol), XPhos Pd G2 (2 mg, 3.37 μmop and potassium phosphate,tribasic (14 mg, 0.067 mmol) in dioxane (200 μl) and water (56 μl) wasevacuated, back filled with nitrogen and then stirred at 80° C. for 1hr. The mixture was diluted with water and ethyl acetate. The phaseswere separated and the organic phase washed with water and brine, driedover sodium sulfate and concentrated. The crude residue was thendissolved in a 1:1 mixture of 4N HCl in dionxane/MeOH (1 mL), stirredfor 30 mins at r.t., then diluted with MeOH purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₈H₃₁F₂N₆O₄ (M+H)⁺: m/z=553.2; Found: 553.2.

Example A. HPK1 Kinase Binding Assay

A stock solution of 1 mM test compound was prepared in DMSO. Thecompound plate was prepared by 3-fold and 11-point serial dilutions. 0.1μL of the compound in DMSO was transferred from the compound plate tothe white 384 well polystyrene plates. The assay buffer contained 50 mMHEPES, pH 7.5, 0.01% Tween-20, 5 mM MgCl₂, 0.01% BSA, and 5 mM DTT. 5 μLof 4 nM active HPK1 (SignalChem M23-11G) prepared in the buffer wasadded to the plate. The enzyme concentration given was based on thegiven stock concentration reported by the vender. 5 μl of 18 nM tracer222 (ThermoFisher PV6121) and 4 nM LanthaScreen Eu-Anti GST antibody(ThermoFisher PV5595) were added. After one hour incubation at 25° C.,the plates were read on a PHERAstar FS plate reader (BMG Labtech). Kivalues were determined.

Compounds of the present disclosure, as exemplified in Examples, showedthe K_(i) values in the following ranges: +=Ki≤100 nM; ++=100 nM<Ki≤500nM; +++=500 nM<Ki≤5000 nM.

TABLE 1 Example Ki, nM  1, Peak 1 +  1, Peak 2 +  2 +  3, Peak 1 +  3,Peak 2 +  4, Peak 1 +  4, Peak 2 +  5, Peak 1 +  5, Peak 2 +  6, Peak1 +  6, Peak 2 +  7, Peak 1 +  7, Peak 2 +  8, Peak 1 +  8, Peak 2 + 9 + 10, Peak 1 + 10, Peak 2 + 11 + 12 + 13 + 14, Peak 1 + 14, Peak 2 +15, Peak 1 + 15, Peak 2 + 16, Peak 1 +++ 16, Peak 2 + 17 + 18, Peak 1 +18, Peak 2 + 19 + 20 + 21 + 22 + 23 + 24 + 25 + 26 + 27 + 28 + 29 ++30 + 31 + 32 + 33 + 34 + 35 + 36 + 37 + 38 + 39 + 40 + 41 + 42 +

Example B. p-SLP76S376 HTRF Assay

One or more compounds of the invention can be tested using thep-SLP76S376 HTRF assay described as follows. Jurkat cells (cultured inRPMI1640 media with 10% FBS) are collected and centrifuged, followed byresuspension in appropriate media at 3×10⁶ cells/mL. The Jurkat cells(35 μL) are dispensed into each well in a 384 well plate. Test compoundsare diluted with cell culture media for 40-fold dilution (adding 39 μLcell culture media into 1 μL compound). The Jurkat cells in the wellplate are treated with the test compounds at various concentrations(adding 5 ul diluted compound into 35 μL Jurkat cells and starting from3 uM with 1:3 dilution) for 1 hour at 37° C., 5% CO₂), followed bytreatment with anti-CD3 (5 μg/mL, OKT3 clone) for 30 min. A 1:25dilution of 100× blocking reagent (from p-SLP76 ser376HTRF kit) with 4×Lysis Buffer (LB) is prepared and 15 μL of the 4×LB buffer with blockingreagent is added into each well and incubated at room temperature for 45mins with gentle shaking. The cell lysate (16 μL) is added into aGreiner white plate, treated with p-SLP76 ser376HTRF reagents (2 μLdonor, 2 ul acceptor) and incubated at 4° C. for overnight. Thehomogeneous time resolved fluorescence (HTRF) is measured on a PHERAstarplate reader the next day. IC₅₀ determination is performed by fittingthe curve of percent inhibition versus the log of the inhibitorconcentration using the GraphPad Prism 5.0 software.

Example C. Isolation of CD4+ or CD8+ T Cells and Cytokine Measurement

Blood samples are collected from healthy donors. CD4+ or CD8+ T cellsare isolated by negative selection using CD4+ or CD8+ enrichment kits(lifetech, USA). The purity of the isolated CD4+ or CD8+ T cells isdetermined by flow cytometry and is routinely >80%. Cells are culturedin RPMI 1640 supplemented with 10% FCS, glutamine and antibiotics(Invitrogen Life Technologies, USA). For cytokine measurement, Jurkatcells or primary CD4+ or CD8+ T cells are plated at 200 k cells/well andare stimulated for 24 h with anti-CD3/anti-CD28 beads in the presence orabsence of testing compounds at various concentrations. 16 μL ofsupernatants are then transferred to a white detection plate andanalyzed using the human IL2 or IFNγ assay kits (Cisbio).

Example D. Treg Assay

One or more compounds can be tested using the Regulatory T-cellproliferation assay described as following. Primary CD4+/CD25− T-cellsand CD4+/CD25+ regulatory T-cells are isolated from human donatedPeripheral Blood Mononuclear Cells, using an isolated kit from ThermoFisher Scientific (11363D). CD4+/CD25-T-cells are labeled with CFSE(Thermo Fisher Scientific, C34554) following the protocol provided bythe vendor. CFSE labeled T-cells and CD4+/CD25+ regulatory T-cells arere-suspended at the concentration of 1×106 cells/mL in RPMI-1640 medium.100 μL of CFSE-labeled T-cells are mixed with or without 50 μL ofCD4+/CD25+ regulatory T-cells, treated with 5 μl of anti-CD3/CD28 beads(Thermo Fisher Scientific, 11132D) and various concentrations ofcompounds diluted in 50 μl of RPMI-1640 medium. Mixed populations ofcells are cultured for 5 days (37° C., 5% CO₂) and proliferation ofCFSE-labeled T-cells is analyzed by BD LSRFortessa X-20 using FITCchannel on the 5th day.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

What is claimed is:
 1. A method for treating a cancer in a patient, saidmethod comprising: administering to the patient a therapeuticallyeffective amount of a compound of Formula (II) or Formula (III):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NOR^(a))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),S(O)₂NR^(c)R^(d) and BR^(h)R^(i); wherein said C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰; Cy¹ is selected from C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryleach has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of the 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰; R³ isselected from Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NOR^(a3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), S(O)₂NR^(c3)R^(d3) andBR^(h3)R^(i3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³; R^(X) is selected from Cy⁴, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(v1),SR^(v1), C(O)R^(w1), C(O)NR^(x1)R^(y1), C(O)OR^(x1), OC(O)R^(w1),OC(O)NR^(x1)R¹¹, NR^(x1)R^(y1), NR^(x1)C(O)R^(w1) NR^(x1)C(O)OR^(v1),NR^(x1)C(O)NR^(x1)R^(y1), C(═NR^(z1))R^(w1), C(═NOR^(v1))R^(w1),C(═NR^(z1))NR^(x1)R^(y1), NR^(x1)C(═NR^(z1))NR^(x1)R^(y1),NR^(x1)S(O)R^(w1), NR^(x1)S(O)₂R^(w1), NR^(x1)S(O)₂NR^(x1)R^(y1),S(O)R^(w1), S(O)NR^(x1)R^(y1), S(O)₂R^(w1), S(O)₂NR^(x1)R^(y1) andBR^(t1)R^(u1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³; Cy³ and Cy⁴ are each independentlyselected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of the 5-10membered heteroaryl and 4-10 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹³; each R⁷ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(c7))R^(b7),C(═NOR^(a7))R^(b7), C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7) S(O)NR^(c7)R^(d7), S(O)₂R^(b7),S(O)₂NR^(c7)R^(d7) and BR^(h7)R^(i7); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁸; each R⁸ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), S(O)₂NR^(c8)R^(d8) and BR^(h8)R^(i8);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁹; each R⁹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,CN, OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9),NR^(c9)R^(d9) NR^(c9)C(O)R^(b9), NR^(c9)C(O)OR^(a9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), and S(O)₂NR^(c9)R^(d9); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1) and BR^(h1)R^(i1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹; each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a11), SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),C(O)OR^(a11), NR^(c11)R^(d11), NR^(c11)C(O)R^(b11),NR^(c11)C(O)OR^(a11), NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11), S(O)NR^(c11)R^(d11),S(O)₂R^(b11), S(O)₂NR^(c11)R^(d11) and BR^(h11)R^(i11); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R¹² is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl,halo, D, CN, OR^(a12), SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),C(O)OR^(a12), NR^(c12)R^(d12), NR^(c12)C(O)R^(b12),NR^(c12)C(O)OR^(a12), NR^(c12)S(O)R^(b12), NR^(c12)S(O)₂R^(b12),NR^(c12)S(O)₂NR^(c12)R^(d12), S(O)R^(b12), S(O)NR^(c12)R^(d12),S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12) and BR^(h12)R^(i12); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R¹³ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a13), SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13),C(O)OR^(a13), OC(O)R^(b13), OC(O)NR^(c13)R^(d13), NR^(c13)R^(d13),NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13), NR^(c13)C(O)NR^(c13)R^(d13),C(═NR^(e13))R^(b13), C(═NOR^(a13))R^(b13), C(═NR^(e13))NR^(c13)R^(d13),NR^(c13)C(═NR^(e13))NR^(c13)R^(d13), NR^(c13)S(O)R^(b13),NR^(c13)S(O)₂R^(b13), NR^(c13)S(O)₂NR^(c13)R^(d13), S(O)R^(b13),S(O)NR^(c13)R^(d13), S(O)₂R^(b13), S(O)₂NR^(c13)R^(d13) andBR^(h13)R^(i13); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁴; each R¹⁴ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a14), SR^(a14), C(O)R^(b14),C(O)NR^(c14)R^(d14), C(O)OR^(a14), NR^(c14)R^(d14), NR^(c14)C(O)R^(b14),NR^(c14)C(O)OR^(a14), NR^(c14)S(O)R^(b14), NR^(c14)S(O)₂R^(b14),NR^(c14)S(O)₂NR^(c14)R^(d14), S(O)R^(b14), S(O)NR^(c14)R^(d14),S(O)₂R^(b14), S(O)₂NR^(c14)R^(d14) and BR^(h14)R^(i14); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁵; each R¹⁵ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,CN, OR^(a15), SR^(a15), C(O)R^(b15), C(O)NR^(c15)R^(d15), C(O)OR^(a15),NR^(c15)R^(d15), NR^(c15)C(O)R^(b15), NR^(c15)C(O)OR^(a15),NR^(c15)S(O)R^(b15), NR^(c15)S(O)₂R^(b15), NR^(c15)S(O)₂NR^(c15)R^(d15),S(O)R^(b15), S(O)NR^(c15)R^(d15), S(O)₂R^(b15), andS(O)₂NR^(c15)R^(d15); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(a), R^(c),and R^(d) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; or any R^(c) and R^(d) attached to the same N atom,together with the N atom to which they are attached, form a 4-10membered heterocycloalkyl group optionally substituted with 1, 2, 3, or4 substituents independently selected from R¹⁰; each R^(b) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁰; each R^(e)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(h) and R^(i) is independently selected fromOH and C₁₋₆ alkoxy; or any R^(h) and R^(i) attached to the same B atomare C₂₋₃ dialkoxy and together with the B atom to which they areattached, form a 5- or 6-membered heterocycloalkyl group optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromC₁₋₆ alkyl; each R^(a1), R^(c1) and R^(d1) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; or any R^(c1) and R^(d1)attached to the same N atom, together with the N atom to which they areattached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; each R^(b1) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R^(e1) is independently selectedfrom H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, aminosulfonyl, C₁₋₆alkylaminosulfonyl and di(C₁₋₆ alkyl)aminosulfonyl; each R^(h1) andR^(i1) is independently selected from OH and C₁₋₆ alkoxy; or any R^(h1)and R^(i1) attached to the same B atom are C₂₋₃ dialkoxy and togetherwith the B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a3), R^(c3)and R^(d3) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³; or any R^(c3) and R^(d3) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹³; each R^(b3) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹³; each R^(e3)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(h3) and R^(i3) is independently selectedfrom OH and C₁₋₆ alkoxy; or any R^(h3) and R^(i3) attached to the same Batom are C₂₋₃ dialkoxy and together with the B atom to which they areattached, form a 5- or 6-membered heterocycloalkyl group optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromC₁₋₆ alkyl; each R^(a7), R^(c7) and R^(d7) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said Cu alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸; or any R^(c7) and R^(d7)attached to the same N atom, together with the N atom to which they areattached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸; each R^(b7) is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸; each R^(e7) is independently selectedfrom H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, aminosulfonyl, C₁₋₆alkylaminosulfonyl and di(C₁₋₆ alkyl)aminosulfonyl; each R^(h7) andR^(i7) is independently selected from OH and C₁₋₆ alkoxy; or any R^(h7)and R^(i7) attached to the same B atom are C₂₋₃ dialkoxy and togetherwith the B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a8), R^(c8)and R^(d8) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁹; or any R^(c8) and R^(d8) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁹; each R^(b8) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁹; each R^(h8)and R^(i8) is independently selected from OH and C₁₋₆ alkoxy; or anyR^(h8) and R^(i8) attached to the same B atom are C₂₋₃ dialkoxy andtogether with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl; each R^(a9),R^(c9) and R^(d9) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(b9) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a11), R^(c11) and R^(d11) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; or any R^(c11) andR^(d11) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹²; each R^(b11) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R^(h11) and R^(i11) isindependently selected from OH and C₁₋₆ alkoxy; or any R^(h11) andR^(i11) attached to the same B atom are C₂₋₃ dialkoxy and together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a12),R^(c12) and R^(d12) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(b12) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl andC₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(h12) and R^(i12) isindependently selected from OH and C₁₋₆ alkoxy; or any R^(h12) andR^(i12) attached to the same B atom are C₂₋₃ dialkoxy and together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a13),R^(c13) and R^(d13) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁴; or any R^(c13) and R^(d13) attached to the same Natom, together with the N atom to which they are attached, form a 4-,5-, 6- or 7-membered heterocycloalkyl group optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁴; each R^(b13)is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁴; eachR^(e13) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(h13) and R^(i13) is independently selectedfrom OH and C₁₋₆ alkoxy; or any R^(h13) and R^(i13) attached to the sameB atom are C₂₋₃ dialkoxy and together with the B atom to which they areattached, form a 5- or 6-membered heterocycloalkyl group optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromC₁₋₆ alkyl; each R^(a14), R^(c14) and R^(d14) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁵; or any R^(c14) and R^(d14)attached to the same N atom, together with the N atom to which they areattached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁵; each R^(b14) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁵; each R^(h14) and R^(i14) isindependently selected from OH and C₁₋₆ alkoxy; or any R^(h14) andR^(i14) attached to the same B atom are C₂₋₃ dialkoxy and together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a15),R^(c15) and R^(d15) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(b15) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(v1), R^(x1), and R^(y1) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹³; or anyR^(x1) and R^(y1) attached to the same N atom, together with the N atomto which they are attached, form a 4-10 membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³; each R^(w1) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹³; each R^(z1) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(t1) and R^(u1) is independently selectedfrom OH and C₁₋₆ alkoxy; or any R^(t1) and R^(u1) attached to the same Batom are C₂₋₃ dialkoxy and together with the B atom to which they areattached, form a 5- or 6-membered heterocycloalkyl group optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromC₁₋₆ alkyl; each R^(g) is independently selected from OH, NO₂, CN, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₃₋₆ cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and m is 1, 2, 3, or 4; and wherein the canceris selected from breast cancer, colorectal cancer, lung cancer, ovariancancer, and pancreatic cancer.
 2. The method of claim 1, wherein thecompound has Formula (II) or Formula (III):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom Cy¹ and NR^(c)R^(d); Cy¹ is selected from 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the4-10 membered heterocycloalkyl and 5-10 membered heteroaryl each has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of the 5-10 membered heteroaryl and 4-10membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁰; R³ isselected from Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3)and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³; R^(X) is selected from C₁₋₆ alkyl, CN,halo, C(O)NR^(x1)R^(y1), and Cy⁴; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹³; Cy³ and Cy⁴ are each independently is selected from C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10 memberedheteroaryl each has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of the 5-10 membered heteroaryl and4-10 membered heterocycloalkyl is optionally substituted by oxo to forma carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³; each R⁷ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 5-10 membered heteroaryl,halo, D, CN, NO₂, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7) and S(O)₂NR^(c7)R^(d7);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁸; each R⁸ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), S(O)₂R^(b8) andS(O)₂NR^(c8)R^(d8); each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, NO₂, OR^(al), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R¹¹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a11), SR^(a11), C(O)R^(b11),C(O)NR^(c11)R^(d11), C(O)OR^(a11), NR^(c11)R^(d11), NR^(c11)C(O)R^(b11),NR^(c11)C(O)OR^(a11), NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11), S(O)NR^(c11)R^(d11),S(O)₂R^(b11) and S(O)₂NR^(c11)R^(d11); each R¹³ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, NO₂, OR^(a13), SR^(a13), C(O)R^(b13),C(O)NR^(c13)R^(d13), C(O)OR^(a13), OC(O)R^(b13), OC(O)NR^(c13)R^(d13),NR^(c13)R^(d13), NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13),NR^(c13)C(O)NR^(c13)R^(d13), NR^(c13)S(O)R^(b13), NR^(c13)S(O)₂R^(b13),NR^(c13)S(O)₂NR^(c13)R^(d13), S(O)R^(b13), S(O)NR^(c13)R^(d13),S(O)₂R^(b13) and S(O)₂NR^(c13)R^(d13); each R^(c) and R^(d) isindependently selected from H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; each R^(b1) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³; each R^(b3) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹³; each R^(a7), R^(c7) andR^(d7) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸; or any R^(c7) and R^(d7) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁸; each R^(b7) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁸; each R^(a8),R^(c8) and R^(d8) is independently selected from H, C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(b8) is independently selected from C₁₋₆ alkyl andC₁₋₆ haloalkyl; each R^(a11), R^(c11) and R^(d11) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(b11) isindependently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(a13),R^(c13) and R^(d13) is independently selected from H, C₁₋₆ alkyl andC₁₋₆ haloalkyl; each R^(b13) is independently selected from C₁₋₆ alkyland C₁₋₆ haloalkyl; each R^(x1) and R^(y1) is independently selectedfrom H and C₁₋₆ alkyl; and m is 1, 2, 3, or
 4. 3. The method of claim 1,wherein the compound has Formula (II) or Formula (III):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is Cy¹; Cy¹is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of the 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; R³ is selected from Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3) NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3) NR^(c3)S(O)R^(b), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3) S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3) andS(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³; R^(X) is selected from C₁₋₆ alkyl, CN,halo, C(O)NR^(x1)R^(y1), and Cy⁴; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹³; Cy³ and Cy⁴ are each independently is selected from C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10 memberedheteroaryl each has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of the 5-10 membered heteroaryl and4-10 membered heterocycloalkyl is optionally substituted by oxo to forma carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³; each R⁷ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7) and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁸; each R⁸ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), S(O)₂R^(b8) and S(O)₂NR^(c8)R^(d8);each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a11), SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),C(O)OR^(a11), NR^(c11)R^(d11), NR^(c11)C(O)R^(b11),NR^(c11)C(O)OR^(a11), NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11), S(O)NR^(c11)R^(d11),S(O)₂R^(b11) and S(O)₂NR^(c11)R^(d11); each R¹³ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, NO₂, OR^(a13), SR^(a13), C(O)R^(b13),C(O)NR^(c13)R^(d13), C(O)OR^(a13), OC(O)R^(b13), OC(O)NR^(c13)R^(d13),NR^(c13)R^(d13), NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13),NR^(c13)C(O)NR^(c13)R^(d13), NR^(c13)S(O)R^(b13), NR^(c13)S(O)₂R^(b13),NR^(c13)S(O)₂NR^(c13)R^(d13), S(O)R^(b13), S(O)NR^(c13)R^(d13),S(O)₂R^(b13) and S(O)₂NR^(c13)R^(d13); each R^(a1), R^(c1) and R^(d1) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; each R^(b1) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; each R^(a3), R^(c3) and R^(d3) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹³; each R^(b3) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹³; each R^(a7),R^(c7) and R^(d7) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸; or any R^(c7) and R^(d7) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁸; each R^(b7) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁸; each R^(a8),R^(c8) and R^(d8) is independently selected from H, C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(b8) is independently selected from C₁₋₆ alkyl andC₁₋₆ haloalkyl; each R^(a11), R^(c11) and R^(d11) is independentlyselected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(b11) isindependently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(a13),R^(c13) and R^(d13) is independently selected from H, C₁₋₆ alkyl andC₁₋₆ haloalkyl; each R^(b13) is independently selected from C₁₋₆ alkyland C₁₋₆ haloalkyl; each R^(x1) and R^(y1) is independently selectedfrom H and C₁₋₆ alkyl; and m is 1, 2, 3, or
 4. 4. The method of claim 1,wherein: R¹ is Cy¹; Cy¹ is selected from 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein the4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰; R³ is selected from Cy³, C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, CN, and C(O)NR^(c3)R^(d3); wherein said C₁₋₆ alkylis optionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³; R^(X) is selected from C₁₋₆ alkyl, CN, halo, andC(O)NR^(x1)R^(y1); Cy³ is selected from C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the4-10 membered heterocycloalkyl and 5-10 membered heteroaryl each has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹³; each R⁷is independently selected from halo and OR^(a7); each R¹⁰ isindependently selected from C₁₋₆ alkyl, OR^(a1), C(O)NR^(c1)R^(d1),NR^(c1)R^(d1), and NR^(c1)C(O)OR^(a1); wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; each R¹¹ is independently selected from OR^(a11) andNR^(c11)R^(d11); each R¹³ is independently selected from C₁₋₆ alkyl,halo, D, CN, and OR^(a13); each R^(a1), R^(c1) and R^(d1) isindependently selected from H and C₁₋₆ alkyl; each R^(a7) isindependently selected from H and C₁₋₆ alkyl; each R^(a11), R^(c11) andR^(d11) is independently selected from H, and C₁₋₆ alkyl; each R^(a13)is independently selected from H, and C₁₋₆ alkyl; each R^(x1) and R^(Y1)is independently selected from H and C₁₋₆ alkyl; and m is 1, 2, 3, or 4.5. The method of claim 1, wherein R¹ is Cy.
 6. The method of claim 1,wherein Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein the 4-10 membered heterocycloalkyland 5-10 membered heteroaryl each has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo; and wherein the 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰.
 7. The method of claim 1, wherein Cy¹is selected from 4-10 membered heterocycloalkyl and 5-10 memberedheteroaryl; wherein a ring-forming carbon atom of the 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo; and wherein the 4-10 membered heterocycloalkyl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.
 8. The method of claim 1,wherein Cy¹ is C₆₋₁₀ aryl optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.
 9. The method of claim 1,wherein Cy¹ is phenyl optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.
 10. The method of claim 1,wherein R¹ is NR^(c)R^(d).
 11. The method of claim 1, wherein each R^(c)and R^(d) is independently selected from H, C₁₋₆ alkyl, and 4-7 memberedheterocycloalkyl, wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, or 3substituents independently selected from R¹⁰.
 12. The method of claim 1,wherein each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c11)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹.
 13. The method of claim 1, wherein each R¹⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1) and NR^(c1)C(O)OR^(a1); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.
 14. The method of claim 1, wherein each R¹⁰ is independentlyselected from C₁₋₆ alkyl, OR^(a1), C(O)NR^(c1)R^(d1) and NR^(c1)R^(d1).15. The method of claim 1, wherein each R¹⁰ is independently selectedfrom C(O)NR^(c1)R^(d1), NR^(c1)R^(d1) and C₁₋₆ alkyl; each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.
 16. The method of claim 1, wherein R^(c1) is selected from H andC₁₋₆ alkyl.
 17. The method of claim 1, wherein R^(d1) is selected from Hand C₁₋₆ alkyl.
 18. The method of claim 1, wherein each R¹¹ isindependently selected from OR^(a11) and NR^(c11)R^(d11).
 19. The methodof claim 1, wherein each R^(a11), R^(c11) and R^(d11) is independentlyselected from H and C₁₋₆ alkyl.
 20. The method of claim 1, whereinR^(a11) is H.
 21. The method of claim 1, wherein R^(c11) is selectedfrom H and C₁₋₆ alkyl.
 22. The method of claim 1, wherein R^(d11) is H.23. The method of claim 1, wherein Cy¹ is selected from2,5-diazabicyclo[2.2.1]heptan-2-yl;5-(ethylcarbamoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl;4-amino-2-(hydroxymethyl)pyrrolidin-1-yl; 3-aminopyrrolidin-1-yl;2,5-diazabicyclo[2.2.1]octan-2-yl; 2-(hydroxymethyl)pyrrolidin-1-yl;morpholino; 6-oxo-2,7-diazaspiro[4.4]nonan-2-yl; 3-aminoazetidin-1-yl;2-(aminomethyl)pyrrolidin-1-yl; pyrrolidin-3-yl; 2-oxopyrrolidin-1-yl;1H-pyrazol-1-yl; o-tolyl; 3-aminopiperidin-1-yl; piperazin-1-yl;pyridin-3-yl; 1-methyl-1H-pyrazol-4-yl; 3-(hydroxymethyl)phenyl;2-(hydroxymethyl)phenyl; 3-((dimethylamino)methyl)phenyl;4-(dimethylamino)piperidin-1-yl;4-hydroxy-2-(aminomethyl)pyrrolidin-1-yl and3-(hydroxymethyl)piperazin-1-yl.
 24. The method of claim 1, wherein Cy¹is selected from 2,5-diazabicyclo[2.2.1]heptan-2-yl;5-(ethylcarbamoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl;4-amino-2-(hydroxymethyl)pyrrolidin-1-yl; 3-aminopyrrolidin-1-yl;2,5-diazabicyclo[2.2.1]octan-2-yl; 2-(hydroxymethyl)pyrrolidin-1-yl;morpholino; 6-oxo-2,7-diazaspiro[4.4]nonan-2-yl; 3-aminoazetidin-1-yl;2-(aminomethyl)pyrrolidin-1-yl; pyrrolidin-3-yl; 2-oxopyrrolidin-1-yl;1H-pyrazol-1-yl; o-tolyl; 3-aminopiperidin-1-yl; piperazin-1-yl;pyridin-3-yl; 1-methyl-1H-pyrazol-4-yl; 3-(hydroxymethyl)phenyl;2-(hydroxymethyl)phenyl; 3-((dimethylamino)methyl)phenyl; and4-(dimethylamino)piperidin-1-yl.
 25. The method of claim 1, wherein Cy¹is selected from 4-hydroxy-2-(aminomethyl)pyrrolidin-1-yl and3-(hydroxymethyl)piperazin-1-yl.
 26. The method of claim 1, wherein R³is selected from Cy³, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), and NR^(c3)C(O)NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³.
 27. The method of claim 1, wherein R³ is selectedfrom Cy³, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³.
 28. The method of claim 1, wherein R³ is optionallysubstituted C₁₋₆ alkyl.
 29. The method of claim 1, wherein R³ is methyl.30. The method of claim 1, wherein R³ is 2-hydroxyethyl.
 31. The methodof claim 1, wherein R³ is 2-methoxyethyl.
 32. The method of claim 1,wherein R³ is 2-fluoroethyl.
 33. The method of claim 1, wherein R³ isCy³.
 34. The method of claim 1, wherein Cy³ is 4-10 memberedheterocycloalkyl or 5-10 membered heteroaryl, each of which isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹³.
 35. The method of claim 1, wherein Cy³ is 4-10membered heterocycloalkyl, which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³.
 36. The method ofclaim 1 wherein Cy³ is tetrahydrofuranyl.
 37. The method of claim 1,wherein Cy³ is 5-10 membered heteroaryl, which is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹³.
 38. Themethod of claim 1, wherein each R¹³ is independently selected from C₁₋₆alkyl, halo, CN and OR^(a13).
 39. The method of claim 1, wherein R¹³ isCN.
 40. The method of claim 1, wherein Cy³ is 3-cyanopyridinyl.
 41. Themethod of claim 1, wherein R^(X) is selected from H, D, Cy⁴, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(v1), SR^(v1),C(O)R^(w1), C(O)NR^(x1)R^(y1), C(O)OR^(x1), OC(O)R^(w1),OC(O)NR^(x1)R^(y1), NR^(x1)R^(y1), NR^(x1)C(O)R^(w1),NR^(x1)C(O)OR^(v1), and NR^(x1)C(O)NR^(x1)R^(y1); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹³.
 42. Themethod of claim 1, wherein R^(X) is selected from H, D, C₁₋₆ alkyl, CN,halo, and C(O)NR^(x1)R^(y1); wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹³.
 43. The method of claim 1, wherein R^(X) is halo.
 44. The method ofclaim 1, wherein R^(X) is F.
 45. The method of claim 1, wherein R^(X) isCN.
 46. The method of claim 1, wherein R^(X) is C₁₋₆ alkyl optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹³.
 47. The method of claim 1, wherein R^(X) is methyl.
 48. The methodof claim 1, wherein R^(X) is C(O)NR^(x1)R^(y1).
 49. The method of claim1, wherein R^(x1) is selected from C₁₋₆ alkyl and H.
 50. The method ofclaim 1, wherein R^(y1) is selected from C₁₋₆ alkyl and H.
 51. Themethod of claim 1, wherein each R⁷ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7) and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁸.
 52. Themethod of claim 1, wherein each R⁷ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a7),SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), and NR^(c7)C(O)NR^(c7)R^(d7);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁸.
 53. The method of claim 1, wherein each R⁷ is independently selectedfrom C₁₋₆ alkyl, 5-10 membered heteroaryl, halo, OR^(a7),C(O)NR^(c7)R^(d7), NR^(c7)R^(d7), wherein said C₁₋₆ alkyl and 5-10membered heteroaryl are each optionally substituted with 1, 2, or 3substituents independently selected from R⁸.
 54. The method of claim 1,wherein each R⁷ is independently selected from halo and OR^(a7).
 55. Themethod of claim 1, wherein R^(a7) is C₁₋₆ alkyl.
 56. The method of claim1, wherein R^(a7) is methyl.
 57. The method of claim 1, wherein each R¹³is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, D, CN, NO₂, OR^(a13), SR^(a13),C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13), OC(O)R^(b13),OC(O)NR^(c13)R^(d13), NR^(c13)R^(d13), NR^(c13)C(O)R^(b13),NR^(c13)C(O)OR^(a13), NR^(c13)C(O)NR^(c13)R^(d13), NR^(c13)S(O)R^(b13),NR^(c13)S(O)₂R^(b13), NR^(c13)S(O)₂NR^(c13)R^(d13), S(O)R^(b13),S(O)NR^(c13)R^(d13), S(O)₂R^(b13) and S(O)₂NR^(c13)R^(d13).
 58. Themethod of claim 1, wherein each R¹³ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN,OR^(a13), SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13),NR^(c13)R^(d13) NR^(c13)C(O)R^(b13), NR^(c13)C(O)OR^(a13) andNR^(c13)C(O)NR^(c13)R^(d13).
 59. The method of claim 1, wherein each R¹³is independently selected from C₁₋₆ alkyl, CN, and OR^(a13).
 60. Themethod of claim 1, wherein the compound has Formula II:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or4.
 61. The method of claim 1, wherein the compound has Formula III:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, or4.
 62. The method of claim 1, wherein the compound is selected from:N-(4-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(1S,4S)—N-Ethyl-5-(7-fluoro-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-1-methyl-1H-indazol-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide;N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)—N-(4-(3-Aminopyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)—N-(4-(3-aminopyrrolidin-1-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)—N-(7-Fluoro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)—N-(7-fluoro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-1-methyl-4-morpholino-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-fluoro-2-methyl-4-morpholino-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-1-methyl-4-(6-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-fluoro-2-methyl-4-(6-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-(3-Aminoazetidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-7-fluoro-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-1-methyl-4-(pyrrolidin-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-1-methyl-4-(2-oxopyrrolidin-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-1-methyl-4-(1H-pyrazol-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-1-methyl-4-o-tolyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-2-methyl-4-o-tolyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)—N-(4-(3-aminopiperidin-1-yl)-7-cyano-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)—N-(4-(3-aminopiperidin-1-yl)-7-cyano-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)-4-(3-aminopiperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-N,1-dimethyl-1H-indazole-7-carboxamide;(R)-4-(3-aminopiperidin-1-yl)-5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-N,2-dimethyl-2H-indazole-7-carboxamide;(R)—N-(4-(3-Aminopyrrolidin-1-yl)-7-fluoro-1-(2-hydroxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(1,7-Dimethyl-4-(piperazin-1-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(2,7-dimethyl-4-(piperazin-1-yl)-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)—N-(4-(3-aminopyrrolidin-1-yl)-1,7-dimethyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-1-methyl-4-(pyridin-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-4-(3-(hydroxymethyl)phenyl)-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(7-Fluoro-4-(2-(hydroxymethyl)phenyl)-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-(3-((Dimethylamino)methyl)phenyl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-(2-hydroxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;andN-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;or a pharmaceutically acceptable salt thereof.
 63. The method of claim1, wherein the compound is selected from:N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)—N-(7-Fluoro-4-(3-(hydroxymethyl)piperazin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-1-(3-cyanopyridin-4-yl)-7-fluoro-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4S)-2-(Aminomethyl)-4-hydroxypyrrolidin-1-yl)-7-fluoro-1-methyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;andN-(4-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-7-fluoro-1-(2-fluoroethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;or a pharmaceutically acceptable salt thereof.
 64. The method of claim1, wherein the compound is selected from:N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-(methoxy-d₃)-3-methylphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(4-amino-2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxy-3-(methylcarbamoyl)phenyl)pyrimidine-4-carboxamide;N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-7-fluoro-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrimidine-4-carboxamide;and(R)—N-(7-Fluoro-1-methyl-4-(methyl(piperidin-3-yl)amino)-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;or a pharmaceutically acceptable salt thereof.
 65. The method of claim1, wherein the compound is(R)—N-(4-(3-aminopyrrolidin-1-yl)-1,7-dimethyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 66. The method of claim1, wherein the compound is(R)—N-(4-(3-aminopyrrolidin-1-yl)-1,7-dimethyl-1H-indazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide.67. The method of claim 1, wherein the cancer is breast cancer.
 68. Themethod of claim 1, wherein the cancer is colorectal cancer.
 69. Themethod of claim 1, wherein the cancer is lung cancer.
 70. The method ofclaim 1, wherein the cancer is ovarian cancer.
 71. The method of claim1, wherein the cancer is pancreatic cancer.